MCL1

Summary

MCL1 (MCL1 apoptosis regulator, BCL2 family member, HGNC:6943) is a protein-coding gene on chromosome 1q21.2, encoding Induced myeloid leukemia cell differentiation protein Mcl-1 (Q07820). Involved in the regulation of apoptosis versus cell survival, and in the maintenance of viability but not of proliferation. It is a selective cancer dependency (DepMap: 63.7% of cell lines).

This gene encodes an anti-apoptotic protein, which is a member of the Bcl-2 family. Alternative splicing results in multiple transcript variants. The longest gene product (isoform 1) enhances cell survival by inhibiting apoptosis while the alternatively spliced shorter gene products (isoform 2 and isoform 3) promote apoptosis and are death-inducing.

Source: NCBI Gene 4170 — RefSeq curated summary.

At a glance

• GWAS associations: 20
• Clinical variants (ClinVar): 11 total
• GTEx eGene: eQTL in 16 tissues, sQTL in 14 (q < 0.05)
• Drug target: yes — 1 curated mechanism-of-action drug; 19 molecules with ChEMBL bioactivity (top 2% of genes corpus-wide)
• Cancer dependency (DepMap): dependent in 63.7% of screened cell lines
• Constraint (gnomAD): pLI 1.00 (loss-of-function intolerant), LOEUF 0.40 (moderately constrained)
• MANE Select transcript: NM_021960
• Interaction hub: 3,734 STRING partners (top 1% of genes corpus-wide)

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6943
Approved symbol	MCL1
Name	MCL1 apoptosis regulator, BCL2 family member
Location	1q21.2
Locus type	gene with protein product
Status	Approved
Aliases	BCL2L3, Mcl-1
Ensembl gene	ENSG00000143384
Ensembl biotype	protein_coding
OMIM	159552
Entrez	4170

Gene structure

Transcript identifiers

Ensembl transcripts: 9 — 6 protein_coding, 2 retained_intron, 1 protein_coding_CDS_not_defined

MANE Select: ENST00000369026

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 3, TSL 2: 1, TSL 5: 1

ENST00000369026, ENST00000307940, ENST00000464132, ENST00000617352, ENST00000620947, ENST00000676522, ENST00000678610, ENST00000678770, ENST00001145715

RefSeq mRNA: 3 — MANE Select: NM_021960 NM_001197320, NM_021960, NM_182763

CCDS: CCDS72909, CCDS956, CCDS957

Canonical transcript exons

ENST00000369026 — 3 exons

Exon	Start	End
ENSE00000959746	150578244	150578491
ENSE00001152267	150578843	150579610
ENSE00001696123	150574558	150577491

Expression profiles

Bgee: expression breadth ubiquitous, 304 present calls, max score 99.64.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 161.3190 / max 4265.9194, expressed in 1828 samples.

Highest expression (Bgee): visceral pleura, parietal pleura, pleura, mucosa of urinary bladder, saphenous vein.

Genetic regulation across tissues (GTEx eQTL / sQTL)

MCL1 is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 16 tissues and its splicing (sQTL) in 14 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

showing 20 of 30 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Whole Blood	eqtl	5.1e-16	-0.16	1:150611627:G:T
Whole Blood	sqtl	1.2e-12	-0.42	1:150561892:T:C
Cells Cultured fibroblasts	sqtl	2.5e-08	-1.56	1:150578851:G:A
Skin Not Sun Exposed Suprapubic	sqtl	2.7e-07	-1.56	1:150578851:G:A
Artery Tibial	sqtl	2.3e-06	+1.40	1:150589567:A:C
Adipose Subcutaneous	sqtl	3.9e-06	-1.25	1:150578851:G:A
Testis	sqtl	4.9e-06	+0.44	1:150561892:T:C
Cells Cultured fibroblasts	eqtl	5.8e-05	+0.29	1:150556846:T:TAA
Esophagus Mucosa	sqtl	7.3e-05	+1.38	1:150578851:G:A
Testis	eqtl	1.0e-03	-0.16	1:150598509:T:G
Esophagus Muscularis	sqtl	1.5e-03	-1.52	1:150548623:A:T
Skin Not Sun Exposed Suprapubic	eqtl	1.9e-03	-0.32	1:150578819:T:C
Breast Mammary Tissue	sqtl	2.3e-03	-1.25	1:150589567:A:C
Muscle Skeletal	sqtl	2.6e-03	+1.09	1:150578851:G:A
Skin Sun Exposed Lower leg	sqtl	2.7e-03	+1.14	1:150578851:G:A
Artery Aorta	eqtl	3.6e-03	+0.20	1:150570652:C:T
Colon Transverse	sqtl	9.0e-03	+1.36	1:150670383:G:A
Nerve Tibial	eqtl	1.3e-02	+0.28	1:150039120:T:C
Lung	sqtl	1.6e-02	-1.01	1:150548623:A:T
Esophagus Mucosa	eqtl	1.6e-02	+0.13	1:150548550:C:G

FANTOM5 promoters

2 alternative TSS:

Promoter ID	TPM avg	Samples expressed
14321	161.2566	1828
14322	0.0625	22

Top tissues by expression

showing 100 of 304 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
visceral pleura	UBERON:0002401	99.64	gold quality
parietal pleura	UBERON:0002400	99.62	gold quality
pleura	UBERON:0000977	99.61	gold quality
mucosa of urinary bladder	UBERON:0001259	99.58	gold quality
saphenous vein	UBERON:0007318	99.52	gold quality
choroid plexus epithelium	UBERON:0003911	99.51	gold quality
mononuclear cell	CL:0000842	99.48	gold quality
epithelium of nasopharynx	UBERON:0001951	99.48	gold quality
monocyte	CL:0000576	99.47	gold quality
cardia of stomach	UBERON:0001162	99.47	gold quality
cervix squamous epithelium	UBERON:0006922	99.47	gold quality
leukocyte	CL:0000738	99.46	gold quality
pharyngeal mucosa	UBERON:0000355	99.40	gold quality
gall bladder	UBERON:0002110	99.40	gold quality
mucosa of paranasal sinus	UBERON:0005030	99.40	gold quality
lower lobe of lung	UBERON:0008949	99.39	gold quality
upper leg skin	UBERON:0004262	99.37	gold quality
pylorus	UBERON:0001166	99.36	gold quality
endothelial cell	CL:0000115	99.34	gold quality
amniotic fluid	UBERON:0000173	99.32	gold quality
nipple	UBERON:0002030	99.31	gold quality
trachea	UBERON:0003126	99.31	gold quality
vermiform appendix	UBERON:0001154	99.27	gold quality
vena cava	UBERON:0004087	99.27	gold quality
superior surface of tongue	UBERON:0007371	99.27	gold quality
caecum	UBERON:0001153	99.26	gold quality
mucosa of stomach	UBERON:0001199	99.24	gold quality
trigeminal ganglion	UBERON:0001675	99.24	gold quality
squamous epithelium	UBERON:0006914	99.23	gold quality
blood	UBERON:0000178	99.21	gold quality
granulocyte	CL:0000094	99.19	gold quality
gingival epithelium	UBERON:0001949	99.17	gold quality
mammary duct	UBERON:0001765	99.15	gold quality
esophagus squamous epithelium	UBERON:0006920	99.15	gold quality
germinal epithelium of ovary	UBERON:0001304	99.14	gold quality
bone marrow cell	CL:0002092	99.08	gold quality
tongue	UBERON:0001723	99.08	gold quality
epithelium of mammary gland	UBERON:0003244	99.08	gold quality
lymph node	UBERON:0000029	99.07	gold quality
bone marrow	UBERON:0002371	99.07	gold quality
pericardium	UBERON:0002407	99.06	gold quality
cervix epithelium	UBERON:0004801	99.04	gold quality
palpebral conjunctiva	UBERON:0001812	99.03	gold quality
smooth muscle tissue	UBERON:0001135	99.00	gold quality
urethra	UBERON:0000057	98.99	gold quality
ventricular zone	UBERON:0003053	98.99	gold quality
seminal vesicle	UBERON:0000998	98.96	gold quality
lower esophagus mucosa	UBERON:0035834	98.96	gold quality
body of tongue	UBERON:0011876	98.94	gold quality
lung	UBERON:0002048	98.93	gold quality
dorsal root ganglion	UBERON:0000044	98.92	gold quality
upper lobe of lung	UBERON:0008948	98.92	gold quality
upper lobe of left lung	UBERON:0008952	98.92	gold quality
gingiva	UBERON:0001828	98.91	gold quality
left uterine tube	UBERON:0001303	98.90	gold quality
right lung	UBERON:0002167	98.88	gold quality
periodontal ligament	UBERON:0008266	98.87	gold quality
renal medulla	UBERON:0000362	98.86	gold quality
penis	UBERON:0000989	98.86	gold quality
peritoneum	UBERON:0002358	98.84	gold quality
omental fat pad	UBERON:0010414	98.84	gold quality
skin of hip	UBERON:0001554	98.83	gold quality
epithelium of esophagus	UBERON:0001976	98.83	gold quality
oral cavity	UBERON:0000167	98.80	gold quality
bone element	UBERON:0001474	98.78	gold quality
descending thoracic aorta	UBERON:0002345	98.78	gold quality
parotid gland	UBERON:0001831	98.76	gold quality
adipose tissue of abdominal region	UBERON:0007808	98.75	gold quality
mammary gland	UBERON:0001911	98.72	gold quality
olfactory bulb	UBERON:0002264	98.72	gold quality
thoracic mammary gland	UBERON:0005200	98.70	gold quality
eye	UBERON:0000970	98.69	gold quality
tendon of biceps brachii	UBERON:0008188	98.67	gold quality
rectum	UBERON:0001052	98.66	gold quality
thoracic aorta	UBERON:0001515	98.66	gold quality
endometrium epithelium	UBERON:0004811	98.66	gold quality
ascending aorta	UBERON:0001496	98.64	gold quality
tongue squamous epithelium	UBERON:0006919	98.62	gold quality
skin of abdomen	UBERON:0001416	98.61	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	98.61	gold quality
type B pancreatic cell	CL:0000169	98.59	gold quality
endometrium	UBERON:0001295	98.59	gold quality
blood vessel layer	UBERON:0004797	98.58	gold quality
superficial temporal artery	UBERON:0001614	98.57	gold quality
colonic epithelium	UBERON:0000397	98.54	gold quality
synovial joint	UBERON:0002217	98.54	gold quality
spleen	UBERON:0002106	98.53	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	98.53	gold quality
tonsil	UBERON:0002372	98.52	gold quality
esophagus mucosa	UBERON:0002469	98.49	gold quality
body of pancreas	UBERON:0001150	98.46	gold quality
right coronary artery	UBERON:0001625	98.46	gold quality
skin of leg	UBERON:0001511	98.41	gold quality
inferior olivary complex	UBERON:0002127	98.40	gold quality
mucosa of sigmoid colon	UBERON:0004993	98.38	gold quality
coronary artery	UBERON:0001621	98.36	gold quality
cauda epididymis	UBERON:0004360	98.36	gold quality
esophagus	UBERON:0001043	98.35	gold quality
zone of skin	UBERON:0000014	98.32	gold quality
left coronary artery	UBERON:0001626	98.30	gold quality

Single-cell (SCXA)

Detected in 14 experiment(s), a significant marker in 12.

Experiment	Marker?	Max mean expression
E-HCAD-4	yes	208.05
E-CURD-88	yes	54.03
E-CURD-46	yes	49.82
E-HCAD-6	yes	39.18
E-HCAD-1	yes	28.96
E-MTAB-9221	yes	26.49
E-CURD-122	yes	23.94
E-HCAD-13	yes	21.83
E-HCAD-10	yes	14.72
E-MTAB-9467	yes	11.35
E-MTAB-9543	yes	10.78
E-GEOD-110499	no	1509.86
E-MTAB-7606	no	446.65
E-ANND-3	no	0.00

HPA expression

RNA tissue specificity: Tissue enhanced

showing 60 of 80 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Bone marrow	tissue	646.6	medium
Liver	tissue	378.3	low
Urinary bladder	tissue	282.1	medium
Gallbladder	tissue	260.8	high
Adipose tissue	tissue	260.3	low
Appendix	tissue	250.1	high
Esophagus	tissue	187.2	medium
Breast	tissue	164.0	medium
Spleen	tissue	161.6	medium
Smooth muscle	tissue	160.1	low
Pancreas	tissue	152.4	medium
Lymph node	tissue	150.8	medium
Tongue	tissue	149.5
Lung	tissue	147.9	medium
Tonsil	tissue	147.3	high
Adrenal gland	tissue	140.9	high
Placenta	tissue	138.0	high
Cervix	tissue	134.6	medium
Thyroid gland	tissue	124.9	high
Skeletal muscle	tissue	122.4	low
Thymus	tissue	120.3
Colon	tissue	119.0	medium
Rectum	tissue	112.9	high
Kidney	tissue	110.5	high
Small intestine	tissue	101.7	high
Duodenum	tissue	93.7	high
Choroid plexus	tissue	93.1
Stomach 1	tissue	90.3	high
Prostate	tissue	90.3	medium
Endometrium 1	tissue	89.6	medium
Vagina	tissue	88.6	medium
Parathyroid gland	tissue	83.9	medium
Retina	tissue	83.5
Spinal cord	tissue	83.4
Ovary	tissue	83.0	medium
Heart muscle	tissue	72.6	medium
Skin 1	tissue	65.6	medium
Locus coeruleus	tissue	61.6
Superior colliculi	tissue	58.6
Substantia nigra	tissue	58.2
Septum	tissue	57.4
Pituitary gland	tissue	56.6
Hypothalamus	tissue	55.7
Pons	tissue	55.3
Thalamus	tissue	54.8
Fallopian tube	tissue	54.7	medium
Cerebral cortex	tissue	54.3	medium
Occipital cortex	tissue	54.3
Putamen	tissue	53.5
Medulla oblongata	tissue	53.5
Periaqueductal gray	tissue	53.4
Midbrain	tissue	53.3
Seminal vesicle	tissue	53.1	medium
Nucleus accumbens	tissue	51.7
Hippocampal formation	tissue	51.5
Entorhinal cortex	tissue	51.5
Hippocampus	tissue	51.4	medium
Somatosensory cortex	tissue	50.5
Basal ganglia	tissue	48.9	medium
Salivary gland	tissue	48.2	medium

Brain sub-regions (HPA Brain Atlas): detected in 192; highest nTPM — Blood vessel (145.5), Posterior thalamic nucleus (109.2), Nucleus ambiguus (96.9), Area parastriata, superior (93.6), Nucleus raphe pallidus (93.1).

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AP1, AR, ATF4, ATF5, ATM, BARX1, BMAL2, CLOCK, DDIT3, DOT1L, E2F1, E2F4, ELK1, ELK4, ESR1, ETS1, FOXC1, GLI2, HBP1, HIF1A, HSF1, IRF4, JUN, KLF2, NFKB1, NFKB, NKX3-1, NKX6-3, NR1H4, NR1I3, NR3C1, PARP1, RELA, SIRT1, SP1, SP3, SPI1, SRF, STAT1, STAT2

miRNA regulators (miRDB)

Targeting MCL1 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

showing 30 of 154 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-5193	100.00	67.26	1744
HSA-MIR-29A-3P	100.00	73.11	1835
HSA-MIR-29B-3P	100.00	73.18	1833
HSA-MIR-29C-3P	100.00	73.15	1833
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-4476	100.00	68.18	2030
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-32-5P	99.98	75.21	1964
HSA-MIR-92A-3P	99.98	75.21	1960
HSA-MIR-92B-3P	99.98	75.25	1955
HSA-MIR-25-3P	99.98	74.60	1817
HSA-MIR-363-3P	99.98	74.72	1821
HSA-MIR-367-3P	99.98	74.83	1819
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-8068	99.98	73.85	2376
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-4666A-3P	99.96	71.71	3434
HSA-MIR-559	99.95	72.28	3609
HSA-MIR-548AB	99.95	71.31	3488
HSA-MIR-548J-3P	99.94	72.61	4881
HSA-MIR-101-3P	99.94	75.03	2230
HSA-MIR-651-3P	99.94	73.48	5177

Functional genomics

gnomAD constraint: pLI 0.997, LOEUF 0.395, missense Z -0.806 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD RMC): no regional variation along ENST00000369026 — one region, missense o/e 1.10. DepMap (CRISPR cell-line fitness): dependent in 63.7% of screened cell lines.

Most-dependent cell lines (DepMap gene-effect, lower = stronger; ≤ −0.5 shown): SNU-16 (-3.316), VCaP (-3.038), SU-DHL-10 (-2.519), Caov-4 (-2.467), TE-8 (-2.42), KMS-20 (-2.356), RERF-GC-1B (-2.33), AML-193 (-2.288), HuH-6 (-2.266), MDA-MB-157 (-2.223), TOV-112D (-2.177), SUP-M2 (-2.117), OCI-LY-19 (-2.113), THP-1 (-2.1), SNU-387 (-2.056).

Literature-anchored findings (GeneRIF, showing 40)

• expression in normal, hyperplastic and carcinomatous human prostate (PMID:11781193)
• Myeloid cell factor-1 (Mcl-1)is a critical survival factor for multiple myeloma. (PMID:11877256)
• Expression of apoptotic regulators and their significance in cervical cancer (PMID:11911971)
• Mcl-1 is over epxressed in anaplastic large cell lymphoma cell lines and tumors. (PMID:12057933)
• Antisense strategy shows that Mcl-1 rather than Bcl-2 or Bcl-x(L) is an essential survival protein of human myeloma cells. (PMID:12070027)
• follicular dendritic cells protect CLL B cells against apoptosis, at least in part through a CD44-dependent mechanism involving up-regulation of Mcl-1 (PMID:12176902)
• inactivation of Mcl-1 by JNK-dependent phosphorylation may be one of the mechanisms through which oxidative stress induces cellular damage in human cells (PMID:12223490)
• related to ratio of p21(WAF)/cyclin A and Jun kinase phosphorylation to apoptosis in human breast carcinomas (PMID:12359245)
• in basal cell carcinoma cells, the upregulation of the anti-apoptotic Mcl-1 protein by interleukin-6 is mainly through the Janus tyrosine kinase/phosphotidyl inositol 3-kinase/Akt, but not the STAT3 pathway. (PMID:12445202)
• interaction of Mcl-1 with tankyrase 1 leads to the modulation of the apoptosis pathway (PMID:12475993)
• The antiapoptotic effect of the in vitro induction of MCL1 expression in Mycobacterium tuberculosis strain H37Rv-infected macrophages promotes the intracellular survival and proliferation of virulent M. tuberculosis. (PMID:12496428)
• activation of STAT3 was dependent on Ser727 phosphorylation, in the absence of detectable Tyr705 phosphorylation; expression of human STAT3 in murine macrophages rescued inhibition of human Mcl-1 promoter gene activation and cell death induced by NaSal (PMID:12637318)
• mechanisms regulating Mcl-1 levels in MM cells are heterogeneous, and are often independent from IL-6 signaling pathways (PMID:12660820)
• the human EAT gene driven by the EF1 alpha promoter induced hyperplasia of Langerhans islet cells and upregulation of Bax and Bag-1 – possible heterodimeric partners for EAT in the anti-apoptotic process (PMID:12782407)
• Following UV treatment, Mcl-1 protein synthesis is blocked, the existing pool of Mcl-1 protein is rapidly degraded by the proteasome, and cytosolic Bcl-xL translocates to the mitochondria (PMID:12783855)
• Mcl-1 is an important factor contributing to the chemoresistance of human melanoma in vivo. (PMID:12787138)
• protein geranylgeranylation is critical for regulating myeloma tumor cell survival, possibly through regulating Mcl-1 expression (PMID:12855556)
• data suggest a role for Mcl-1 in protecting endothelial cells against Stx-1-induced apoptosis (PMID:12901848)
• Respiratory syncytial virus mediated the strong induction of antiapoptotic factors of the Bcl-2 family, especially Mcl-1, which might account for the delayed induction of apoptosis in RSV-infected cells. (PMID:12915532)
• fMLP-stimulated neutrophils coordinate the regulation of FOXO transcription factors and the survival factor Mcl-1, a mechanism that may allow neutrophils to alter their survival. (PMID:12960271)
• restoration of MCL-1 expression rescued infected cells from E1A-induced apoptosis (PMID:14633975)
• IL-15 does not increase IL-1alpha or IL-1beta production but induces IL-1Ra release, increases myeloid cell differentiation factor-1 stability, decreases the activity of caspase-3 and caspase-8, resulting in an inhibition of vimentin cleavage (PMID:14982947)
• Mcl-1L degradation by either GrB or caspase-3 interferes with Bim sequestration by Mcl-1L (PMID:15014070)
• These results are consistent with a model in which p53 and Mcl1 have opposing effects on mitochondrial apoptosis by interacting with, and modulating the activity of, the death effector Bak. (PMID:15077116)
• Profound changes in the rate of neutrophil apoptosis following Granulocyte macrophage colony-stimulating factor signaling occur via dynamic changes in the rate of Mcl-1 turnover via the proteasome. (PMID:15078892)
• Mcl-1 function is an effective means of inducing apoptosis in Mcl-1-positive B-cell lymphoma. (PMID:15122313)
• The MCL-1 promoter insertion may identify a high-risk group of CD38-negative CLL patients (PMID:15126604)
• VEGF-induced MM cell proliferation and survival are mediated via Mcl-1; VEGF up-regulates Mcl-1 expression in a time- and dose-dependent manner in 3 human MM cell lines and MM patient cells (PMID:15217829)
• MCL1 is subject to multiple, separate, post-translational phosphorylation events, produced in living versus dying cells at ERK-inducible versus ERK-independent sites (PMID:15241487)
• the fortilin-MCL1 interaction increases cellular resistance to apoptosis by allowing MCL1, an independently antiapoptotic protein, to stabilize another independently antiapoptotic protein, fortilin (PMID:15262975)
• drug sensitivities of CLL leukemic cells correlated inversely with Mcl-1 levels; results suggest that Mcl-1 may contribute to cell survival in CLL; an inverse correlation was found between Mcl-1 expression and Rai stage (PMID:15370246)
• Cleavage of Mcl-1 by caspases modifies its subcellular localization, increases its association with Bim and inhibits its antiapoptotic function. (PMID:15378010)
• Mcl-1 solution structure and analysis of binding by proapoptotic BH3-only ligands (PMID:15550399)
• SDF-1/CXCL12 enhanced cell survival in synergy with other cytokines involves activation of CREB and induction of Mcl-1 and c-Fos (PMID:15588513)
• Overexpression of Mcl-1 protected hepatoma cells against apoptosis induced by tert-butyl hydroperoxide. (PMID:15611089)
• Mcl-1 accumulation is an unwanted molecular consequence of exposure to proteasome inhibitors, which slows down their proapoptotic effects (PMID:15613543)
• MCL-1 is a BCR/ABL-dependent survival factor and interesting target in chronic myeloid leukemia. (PMID:15626746)
• removal of N-terminal domains of Bid by caspase-8 and Mcl-1 by caspase-3 enables the maximal mitochondrial perturbation that potentiates TRAIL-induced apoptosis (PMID:15637055)
• Knockdown results in a significant level of apoptosis in the absence of external apoptotic stimulation (PMID:15713684)
• Mcl-1 is induced by signaling through the B-cell receptor, which promotes survival of chronic lymphocytic leukemia B cells (PMID:15728130)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	mcl1b	ENSDARG00000008363
danio_rerio	mcl1a	ENSDARG00000009779
mus_musculus	Mcl1	ENSMUSG00000038612
rattus_norvegicus	Mcl1	ENSRNOG00000063678
drosophila_melanogaster	Debcl	FBGN0029131
drosophila_melanogaster	Buffy	FBGN0040491

Paralogs (8): BAK1 (ENSG00000030110), BAX (ENSG00000087088), BCL2L2 (ENSG00000129473), BCL2L10 (ENSG00000137875), BCL2A1 (ENSG00000140379), BCL2L1 (ENSG00000171552), BCL2 (ENSG00000171791), BOK (ENSG00000176720)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:101769) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 55 distinct phenotype terms.

Mouse phenotype (MP)	Records
decreased double-negative T cell number	3
abnormal B cell differentiation	2
decreased T cell number	2
decreased double-positive T cell number	2
increased T cell apoptosis	2
decreased CD8-positive, alpha-beta T cell number	2
decreased hematocrit	1
decreased neutrophil cell number	1
absent pre-B cells	1
decreased granulocyte number	1
decreased mast cell number	1
small spleen	1
enlarged lymph nodes	1
decreased thymocyte number	1
anophthalmia	1
microphthalmia	1
embryonic growth arrest	1
arrested B cell differentiation	1
thymus hypoplasia	1
arrested T cell differentiation	1
decreased inflammatory response	1
hydrocephaly	1
abnormal eye morphology	1
abnormal T cell differentiation	1
abnormal lymph node morphology	1

+30 more (showing top 25).

Additional cross-species homologs

Sequence homologs in species beyond Ensembl Compara’s model organisms, by Diamond local protein alignment (% sequence identity; best hit per species). Lower-identity rows are more distant homologs. The matched accessions’ gene symbols aren’t in biobtree yet, so each row shows the UniProt accession.

Organism	UniProt	Identity	Method
Bos taurus	O02703	97.4%	Diamond
Coturnix japonica	Q90343	96.6%	Diamond
Gallus gallus	Q90ZN1	96.6%	Diamond
Felis catus	Q7YRZ9	88.9%	Diamond
Canis lupus familiaris	Q8HYS5	87.1%	Diamond
Fowlpox virus strain NVSL	Q9J5G4	39.2%	Diamond

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
ADAMTSL4-AS2	ncRNA	100289061
MIR4257	ncRNA	100422997
ADAMTSL4	protein-coding	54507
ADAMTSL4-AS1	ncRNA	574406
ENSA	protein-coding	2029
GOLPH3L	protein-coding	55204
HORMAD1	protein-coding	84072

Protein

Protein identifiers

Induced myeloid leukemia cell differentiation protein Mcl-1 — Q07820 (reviewed: Q07820)

Alternative names: Bcl-2-like protein 3, Bcl-2-related protein EAT/mcl1, mcl1/EAT

All UniProt accessions (3): A0A087WT64, A0A7I2V2W2, Q07820

UniProt curated annotations — full annotation on UniProt →

Function. Involved in the regulation of apoptosis versus cell survival, and in the maintenance of viability but not of proliferation. Mediates its effects by interactions with a number of other regulators of apoptosis. Isoform 1 inhibits apoptosis. Isoform 2 promotes apoptosis.

Subunit / interactions. Interacts with HIF3A (via C-terminus domain). Interacts with BAD, BOK, BIK and BMF. Interacts with PMAIP1. Interacts with BBC3. Isoform 1 interacts with BAX, BAK1 and TPT1. Heterodimer of isoform 1 and isoform 2. Homodimers of isoform 1 or isoform 2 are not detected. Isoform 2 does not interact with pro-apoptotic BCL2-related proteins. Interacts with RTL10/BOP. Interacts with BCL2L11; may sequester BCL2L11 to prevent its pro-apoptotic activity. Interacts with GIMAP5 and HSPA8/HSC70; the interaction between HSPA8 and MCL1 is impaired in the absence of GIMAP5.

Subcellular location. Membrane. Cytoplasm. Mitochondrion. Nucleus. Nucleoplasm.

Post-translational modifications. Cleaved by CASP3 during apoptosis. In intact cells cleavage occurs preferentially after Asp-127, yielding a pro-apoptotic 28 kDa C-terminal fragment. Rapidly degraded in the absence of phosphorylation on Thr-163 in the PEST region. Phosphorylated on Ser-159, by GSK3, in response to IL3/interleukin-3 withdrawal. Phosphorylation at Ser-159 induces ubiquitination and proteasomal degradation, abrogating the anti-apoptotic activity. Treatment with taxol or okadaic acid induces phosphorylation on additional sites. Ubiquitinated. Ubiquitination is induced by phosphorylation at Ser-159. Deubiquitinated by USP20; leading to increased stability.

Induction. Expression increases early during phorbol ester-induced differentiation along the monocyte/macrophage pathway in myeloid leukemia cell line ML-1. Rapidly up-regulated by CSF2 in ML-1 cells. Up-regulated by heat shock-induced differentiation. Expression increases early during retinoic acid-induced differentiation.

Similarity. Belongs to the Bcl-2 family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q07820-1	1, MCL1L, MCL-1L	yes
Q07820-2	2, Delta S, MCL-1S, TM

RefSeq proteins (3): NP_001184249, NP_068779, NP_877495 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002475	Bcl2-like	Family
IPR013281	Apop_reg_Mc1	Family
IPR020717	Bcl2_BH1_motif_CS	Conserved_site
IPR020726	Bcl2_BH2_motif_CS	Conserved_site
IPR020728	Bcl2_BH3_motif_CS	Conserved_site
IPR026298	Bcl-2_fam	Family
IPR036834	Bcl-2-like_sf	Homologous_superfamily
IPR046371	Bcl-2_BH1-3	Domain

Pfam: PF00452

UniProt features (56 total): helix 16, mutagenesis site 14, cross-link 5, modified residue 4, region of interest 3, sequence variant 3, short sequence motif 3, site 2, splice variant 2, compositionally biased region 2, chain 1, transmembrane region 1

Structure

Experimental structures (PDB)

showing 30 of 148 structures by resolution:

PDB	Title	Method	Resolution (Å)
8VJP	Histidine-covalent stapled alpha-helical peptide (155H1) targeting hMcl-1	X-RAY DIFFRACTION	1.13
9PQ7	MBP-Mcl1 in complex with ligand 21b	X-RAY DIFFRACTION	1.24
9PQ5	MBP-Mcl1 in complex with ligand 8	X-RAY DIFFRACTION	1.28
6UDV	X-ray co-crystal structure of compound 3 bound to human Mcl-1	X-RAY DIFFRACTION	1.35
9UGP	Crystal structure of MCL-1 in complex with HRK BH3	X-RAY DIFFRACTION	1.39
8G3S	MBP-Mcl1 in complex with ligand 11	X-RAY DIFFRACTION	1.4
5W89	Crystal structure of human Mcl-1 in complex with modified Bim BH3 peptide SAH-MS1-18	X-RAY DIFFRACTION	1.42
5C3F	Crystal structure of Mcl-1 bound to BID-MM	X-RAY DIFFRACTION	1.43
8G3X	MBP-Mcl1 in complex with ligand 32	X-RAY DIFFRACTION	1.46
8H7B	The crystal structure of human mcl1 kinase domain in complex with MCL1-M-EBA	X-RAY DIFFRACTION	1.46
8SVY	MBP-Mcl1 in complex with ligand 10	X-RAY DIFFRACTION	1.47
6OQD	Crystal structure of Mcl1 with inhibitor 8	X-RAY DIFFRACTION	1.48
5FC4	Mcl-1 complexed with small molecule inhibitor	X-RAY DIFFRACTION	1.5
6UDT	X-ray co-crystal structure of compound 10 bound to human Mcl-1	X-RAY DIFFRACTION	1.5
4HW4	Discovery of potent Mcl-1 inhibitors using fragment-based methods and structure-based …	X-RAY DIFFRACTION	1.53
9PQ6	MBP-Mcl1 in complex with ligand 12	X-RAY DIFFRACTION	1.53
2NL9	Crystal structure of the Mcl-1:Bim BH3 complex	X-RAY DIFFRACTION	1.55
4WMU	STRUCTURE OF MBP-MCL1 BOUND TO ligand 2 AT 1.55A	X-RAY DIFFRACTION	1.55
8EKX	Structure of MBP-Mcl-1 in complex with MIK665	X-RAY DIFFRACTION	1.55
6UA3	Human Mcl-1 in complex with a modified Bim BH3 peptide	X-RAY DIFFRACTION	1.55
8T6F	Crystal structure of human MBP-Myeloid cell leukemia 1 (Mcl-1) in complex with BRD810 …	X-RAY DIFFRACTION	1.56
4BPJ	Mcl-1 bound to alpha beta Puma BH3 peptide 3	X-RAY DIFFRACTION	1.6
6FS1	MCL1 in complex with an indole acid ligand	X-RAY DIFFRACTION	1.6
6O6F	Co-crystal structure of Mcl1 with inhibitor	X-RAY DIFFRACTION	1.6
6OQB	Co-crystal structure of Mcl1 with inhibitor 10	X-RAY DIFFRACTION	1.6
6QFQ	Structure of human Mcl-1 in complex with indole acid inhibitor	X-RAY DIFFRACTION	1.6
9Z3V	Histidine-covalent 165G1 targeting hMcl-1	X-RAY DIFFRACTION	1.6
6P3P	Crystal structure of Mcl-1 in complex with compound 65	X-RAY DIFFRACTION	1.61
3KJ0	Mcl-1 in complex with Bim BH3 mutant I2dY	X-RAY DIFFRACTION	1.7
4WMR	STRUCTURE OF MCL1 BOUND TO BRD inhibitor ligand 1 AT 1.7A	X-RAY DIFFRACTION	1.7

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q07820-F1	65.28	0.31

Antibody-complex structures (SAbDab)

7 antibodies co-crystallized with this protein: 5MES, 5MEV, 6QB3, 6QB4, 6QB6, 6QFC, 8AV9

Human Protein Atlas

Protein class: Predicted membrane proteins, Predicted intracellular proteins, Plasma proteins, Cancer-related genes, Candidate cancer biomarkers, Essential proteins

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): mitochondria

Antibody reliability (HPA): IH enhanced · IF enhanced

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (2)

Position	Role
127–128	cleavage; by caspase-3
157–158	cleavage; by caspase-3

Post-translational modifications (9)

Type	Positions
Phosphoserine	121, 159, 162
Phosphothreonine	163
Glycyl lysine isopeptide (lys-gly) (interchain with g-cter in ubiquitin)	5, 40, 136, 194, 197

Mutagenesis-validated functional residues (14)

Position	Phenotype
5	reduced ubiquitination.
40	reduced ubiquitination.
127	abolishes formation of 28 and 17 kda cleavage products by casp3. abolishes cleavage by caspase-3; when associated with a-157.
136	reduced ubiquitination.
157	abolishes formation of 23 and 21 kda cleavage products by casp3. abolishes cleavage by caspase-3; when associated with a-127.
159	loss of phosphorylation by gsk3 and loss of ubiquitination increasing protein stability.
162	abolishes mitochondrial localization and decreases stability.
162	no effect.
163	no effect on mitochondrial localization.
163	abolishes phosphorylation by mapk. no effect on phosphorylation induced by okadaic acid or taxol.
194	reduced ubiquitination.
197	reduced ubiquitination.
208	no effect on ubiquitination.
234	no effect on ubiquitination.

Function

Pathways and Gene Ontology

Reactome pathways

2 curated (TAS) of 8; 4 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

8 pathways:

ID	Pathway	Evidence
R-HSA-9725370	Signaling by ALK fusions and activated point mutants ⚕	curated
R-HSA-6785807	Interleukin-4 and Interleukin-13 signaling	curated
R-HSA-1643685	Disease ⚕	—
R-HSA-5663202	Diseases of signal transduction by growth factor receptors and second messengers ⚕	—
R-HSA-9700206	Signaling by ALK in cancer ⚕	—
R-HSA-1280215	Cytokine Signaling in Immune system	—
R-HSA-168256	Immune System	—
R-HSA-449147	Signaling by Interleukins	—

MSigDB gene sets: 491 (showing top): GOBP_REGULATION_OF_AUTOPHAGY, WANG_CLIM2_TARGETS_UP, MCLACHLAN_DENTAL_CARIES_UP, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, GOBP_RESPONSE_TO_PEPTIDE, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, MORI_IMMATURE_B_LYMPHOCYTE_UP, GOBP_EXTRINSIC_APOPTOTIC_SIGNALING_PATHWAY, GENTILE_RESPONSE_CLUSTER_D3, ADDYA_ERYTHROID_DIFFERENTIATION_BY_HEMIN, AMIT_SERUM_RESPONSE_40_MCF10A, CTATGCA_MIR153, NAGASHIMA_NRG1_SIGNALING_UP, BAKER_HEMATOPOIESIS_STAT3_TARGETS, BILD_HRAS_ONCOGENIC_SIGNATURE

GO Biological Process (22): cell fate determination (GO:0001709), release of cytochrome c from mitochondria (GO:0001836), DNA damage response (GO:0006974), mitochondrial fusion (GO:0008053), intrinsic apoptotic signaling pathway in response to DNA damage (GO:0008630), negative regulation of autophagy (GO:0010507), cellular homeostasis (GO:0019725), response to cytokine (GO:0034097), regulation of apoptotic process (GO:0042981), positive regulation of apoptotic process (GO:0043065), negative regulation of apoptotic process (GO:0043066), positive regulation of neuron apoptotic process (GO:0043525), extrinsic apoptotic signaling pathway in absence of ligand (GO:0097192), positive regulation of oxidative stress-induced neuron intrinsic apoptotic signaling pathway (GO:1903378), negative regulation of anoikis (GO:2000811), negative regulation of extrinsic apoptotic signaling pathway in absence of ligand (GO:2001240), apoptotic process (GO:0006915), cell differentiation (GO:0030154), transmembrane transport (GO:0055085), protein transmembrane transport (GO:0071806), regulation of intracellular signal transduction (GO:1902531), regulation of apoptotic signaling pathway (GO:2001233)

GO Molecular Function (6): transmembrane protein transporter activity (GO:0008320), channel activity (GO:0015267), protein heterodimerization activity (GO:0046982), BH3 domain binding (GO:0051434), protein binding (GO:0005515), BH domain binding (GO:0051400)

GO Cellular Component (8): nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), mitochondrion (GO:0005739), mitochondrial outer membrane (GO:0005741), cytosol (GO:0005829), membrane (GO:0016020), Bcl-2 family protein complex (GO:0097136)

Reactome top-level categories

6 top-level categories:

Category	Pathways
Signaling by Interleukins	1
Signaling by ALK in cancer	1
Immune System	1
Cytokine Signaling in Immune system	1
Disease	1
Diseases of signal transduction by growth factor receptors and second messengers	1

GO top-level categories

58 GO namespaces:

Category	Terms
cellular anatomical structure	4
apoptotic process	3
cellular developmental process	2
apoptotic signaling pathway	2
regulation of apoptotic process	2
intracellular membrane-bounded organelle	2
cytoplasm	2
cell fate commitment	1
apoptotic mitochondrial changes	1
cellular response to stress	1
mitochondrion organization	1
organelle fusion	1
DNA damage response	1
intrinsic apoptotic signaling pathway	1
autophagy	1
negative regulation of catabolic process	1
regulation of autophagy	1
homeostatic process	1
response to peptide	1
regulation of programmed cell death	1
positive regulation of programmed cell death	1
negative regulation of programmed cell death	1
positive regulation of apoptotic process	1
regulation of neuron apoptotic process	1
neuron apoptotic process	1
signal transduction in absence of ligand	1
extrinsic apoptotic signaling pathway	1
neuron intrinsic apoptotic signaling pathway in response to oxidative stress	1
positive regulation of neuron apoptotic process	1
positive regulation of oxidative stress-induced intrinsic apoptotic signaling pathway	1
regulation of oxidative stress-induced neuron intrinsic apoptotic signaling pathway	1
negative regulation of apoptotic process	1
anoikis	1
regulation of anoikis	1
extrinsic apoptotic signaling pathway in absence of ligand	1
negative regulation of signal transduction in absence of ligand	1
negative regulation of extrinsic apoptotic signaling pathway	1
regulation of extrinsic apoptotic signaling pathway in absence of ligand	1
programmed cell death	1
execution phase of apoptosis	1
transport	1
cellular process	1
protein transport	1
transmembrane transport	1
macromolecule transmembrane transporter activity	1
protein transmembrane transport	1
protein transporter activity	1
passive transmembrane transporter activity	1
protein dimerization activity	1
BH domain binding	1
death domain binding	1
binding	1
protein domain specific binding	1
nuclear lumen	1
intracellular anatomical structure	1
mitochondrial membrane	1
organelle outer membrane	1
protein-containing complex	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 16 of 36 annotations. The rest are phylogenetic / computational / electronic (IEA).

16 experimentally-supported GO terms:

GO term	NS	Evidence
DNA damage response	BP	mutant phenotype
extrinsic apoptotic signaling pathway in absence of ligand	BP	mutant phenotype
negative regulation of anoikis	BP	mutant phenotype
negative regulation of apoptotic process	BP	direct assay
negative regulation of autophagy	BP	mutant phenotype
negative regulation of extrinsic apoptotic signaling pathway in absence of ligand	BP	mutant phenotype
positive regulation of apoptotic process	BP	direct assay
positive regulation of oxidative stress-induced neuron intrinsic apoptotic signaling pathway	BP	genetic interaction
regulation of apoptotic process	BP	direct assay
response to cytokine	BP	direct assay
Bcl-2 family protein complex	CC	direct assay
membrane	CC	direct assay
mitochondrion	CC	direct assay
nucleus	CC	direct assay
BH3 domain binding	MF	physical interaction
protein heterodimerization activity	MF	physical interaction

Protein interactions and networks

STRING

showing 15 of 3,734 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MCL1	BCL2L11	O43521	925
MCL1	BCL2L2-PABPN1	Q92843	880
MCL1	PMAIP1	Q13794	880
MCL1	BMF	Q96LC9	873
MCL1	BOK	Q9UMX3	862
MCL1	XIAP	P98170	841
MCL1	CASP3	P42574	838
MCL1	STAT3	P40763	814
MCL1	BIK	Q13323	809
MCL1	CASP9	P55211	803
MCL1	CYCS	P00001	802
MCL1	BAX	P55269	801
MCL1	TP53	P04637	767
MCL1	BIRC5	O15392	767
MCL1	HRK	O00198	765

IntAct

Human interaction partners of MCL1 in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

showing 30 of 34 partners by confidence:

Partner	Interaction type	MIscore	Records
BAK1	physical association	0.960	12
BCL2L11	association	0.950	15
BAX	association	0.910	6
HUWE1	association	0.880	10
PMAIP1	direct interaction	0.850	3
BBC3	direct interaction	0.810	3
BID	direct interaction	0.700	2
USP9X	direct interaction	0.680	6
PRKAB2	association	0.640	3
BMF	physical association	0.560	3
KCNF1	physical association	0.560	3
STX8	physical association	0.560	3
AKT1	physical association	0.550	3
PRKAG1	association	0.530	1
RTL10	physical association	0.500	1
CAV1	physical association	0.460	3
BIK	direct interaction	0.440	1
TNKS2	direct interaction	0.440	1
BECN1	physical association	0.400	2
SEPTIN9	physical association	0.400	1
UHRF2	physical association	0.400	1
CHRM4	physical association	0.370	1
HRK	physical association	0.370	1
PCNA	physical association	0.370	1
HSPD1	colocalization	0.350	1
FBXW7	proximity	0.270	4
SMAD4	proximity	0.270	4
SPOP	proximity	0.270	4
BRAF	proximity	0.270	1
EGFR	proximity	0.270	1

BioGRID (400 interactions; top human partners by supporting records): HUWE1 (Affinity Capture-Western; 32 records), BCL2L11 (Protein-peptide; 25 records), PMAIP1 (Protein-peptide; 23 records), BAK1 (Affinity Capture-Western; 21 records), USP9X (Affinity Capture-Western; 15 records), FBXW7 (Biochemical Activity; 14 records), BBC3 (Protein-peptide; 13 records), BAX (Co-crystal Structure; 10 records), BID (Affinity Capture-Western; 8 records), USP13 (Affinity Capture-Western; 7 records), TRIM11 (Affinity Capture-MS; 6 records), BCL2L1 (Negative Genetic; 5 records), BTRC (Affinity Capture-Western; 5 records), USP17L2 (Affinity Capture-Western; 5 records), BMF (Protein-peptide; 4 records)

SIGNOR signaling

showing 25 of 28 signaling interactions:

A	Effect	B	Mechanism
BBC3	down-regulates	MCL1	binding
GSK3B	down-regulates	MCL1	phosphorylation
MCL1	down-regulates	BAK1	binding
MCL1	down-regulates	BAX	binding
CDK1	“down-regulates quantity by destabilization”	MCL1	phosphorylation
MAPK1	up-regulates	MCL1	phosphorylation
MAPK3	up-regulates	MCL1	phosphorylation
MAPK8	up-regulates	MCL1	phosphorylation
N-[4-(2-tert-butylphenyl)sulfonylphenyl]-2,3,4-trihydroxy-5-[(2-propan-2-ylphenyl)methyl]benzamide	down-regulates	MCL1	“chemical inhibition”
CyclinB/CDK1	“down-regulates quantity by destabilization”	MCL1	phosphorylation
GSK3A	“down-regulates quantity by destabilization”	MCL1	phosphorylation
DOT1L	“up-regulates quantity by expression”	MCL1	“transcriptional regulation”
NPTX1	“down-regulates quantity”	MCL1
LGALS3	“up-regulates quantity by stabilization”	MCL1
PRKCH	“up-regulates quantity by stabilization”	MCL1
HUWE1	“down-regulates quantity by destabilization”	MCL1	ubiquitination
PSMB8	“down-regulates quantity by destabilization”	MCL1
Gbeta	up-regulates	MCL1	phosphorylation
ERK1/2	up-regulates	MCL1	phosphorylation
MARCHF5	“down-regulates quantity by destabilization”	MCL1	ubiquitination
TRAF6	“up-regulates activity”	MCL1	ubiquitination
DYRK1A	“up-regulates quantity”	MCL1	phosphorylation
GSK3B	“down-regulates quantity by destabilization”	MCL1	phosphorylation
TRIM17	“down-regulates quantity by destabilization”	MCL1	polyubiquitination
“Obatoclax mesylate”	“down-regulates activity”	MCL1	“chemical inhibition”

Protein complexes (CORUM) (3)

Experimentally-characterized complexes this protein is a subunit of (★ = the complex contains a known drug target).

3 complexes by size:

Complex	Subunits	Members
★ BAX-BCL2-MCL1 complex	3	BAX, BCL2, MCL1
★ BCL2-MCL1 complex	2	BCL2, MCL1
MCL1-BAK1 complex	2	BAK1, MCL1

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 34 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Activation of BH3-only proteins	6	102.7×	1e-09
TP53 Regulates Transcription of Genes Involved in Cytochrome C Release	5	93.8×	1e-07
Intrinsic Pathway for Apoptosis	8	80.8×	2e-11
FOXO-mediated transcription	5	57.9×	1e-06
Apoptosis	8	46.3×	9e-10
Programmed Cell Death	8	40.4×	1e-09
TP53 Regulates Metabolic Genes	5	22.4×	9e-05
Transcriptional Regulation by TP53	7	15.0×	1e-05

GO biological processes:

GO term	Partners	Fold	FDR
positive regulation of release of cytochrome c from mitochondria	10	225.3×	1e-19
apoptotic mitochondrial changes	5	130.4×	5e-08
release of cytochrome c from mitochondria	6	123.9×	1e-09
positive regulation of intrinsic apoptotic signaling pathway	8	113.3×	1e-12
positive regulation of protein-containing complex assembly	8	79.3×	2e-11
intrinsic apoptotic signaling pathway	5	52.7×	4e-06
cellular response to UV	5	43.5×	9e-06
positive regulation of neuron apoptotic process	5	40.0×	1e-05

Disease & clinical

Genetic variants

Variant evidence for MCL1: 11 ClinVar records (0 pathogenic / likely pathogenic); 20 GWAS associations.

ClinVar

11 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	3
Likely benign	4
Benign	0

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 27 predictions of 204):

Position(s)	Effect	Δscore	Sites
1:150578305	donor_gain	1.0000
1:150578841–150578842	donor_loss	1.0000	4
1:150577492–150577493	acceptor_loss	0.9900	6
1:150578242–150578243	donor_loss	0.9900	6
1:150578492–150578493	acceptor_loss	0.9900	5
1:150578842	donor_loss	0.9900
1:150578390	donor_gain	0.9800
1:150578492	acceptor_loss	0.9800
1:150578280	donor_loss	0.9700
1:150578286	donor_gain	0.9100

AlphaMissense

844 missense substitutions predicted likely pathogenic (of 2,236 scored), across 189 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
M231	9	0.972	0.999
H224	8	0.996	0.999
F254	8	0.993	0.999
D256	8	0.992	0.999
F270	8	0.992	0.999
F319	8	0.992	1.000
F315	8	0.986	0.999
F228	8	0.983	1.000
F318	8	0.964	1.000
N260	8	0.963	0.999
D323	8	0.963	0.988
F335	8	0.957	0.997
D242	8	0.923	0.972
N13	8	0.875	0.984
D127	8	0.841	0.945
W261	7	0.999	1.000
W305	7	0.999	1.000
W312	7	0.998	1.000
R263	7	0.997	1.000
E325	7	0.964	0.993

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

Human Protein Atlas survival analysis — favorable = higher expression predicts better survival.

1 prognostic cancer types:

Cancer	Prognostic	p-value
Kidney Renal Clear Cell Carcinoma (TCGA)	favorable	0.000696

Disease associations

OMIM: gene MIM:159552 | disease phenotypes:

GWAS associations

20 associations:

Study	Trait	p-value
GCST007429_110	Lung function (FVC)	2e-31
GCST007432_105	FEV1	2e-21
GCST010002_27	Refractive error	3e-15
GCST004624_198	Sum eosinophil basophil counts	4e-11
GCST001266_1	Melanoma	9e-11
GCST005977_25	Monocyte count	1e-10
GCST009801_1	Coffee consumption	1e-10
GCST004606_122	Eosinophil count	2e-10
GCST90002390_491	Mean corpuscular hemoglobin	8e-10
GCST008480_2	Lung function (FEV1)	4e-9
GCST008482_2	Lung function (FVC)	6e-9
GCST001966_1	Rhegmatogenous retinal detachment	1e-7
GCST011947_44	White matter hyperintensity volume	1e-7
GCST006585_305	Blood protein levels	2e-7
GCST005196_173	Coronary artery disease	3e-7
GCST011946_25	White matter hyperintensity volume	7e-7
GCST009597_205	Multiple sclerosis	1e-6
GCST011950_15	White matter hyperintensity volume (adjusted for hypertension)	1e-6
GCST011949_38	White matter hyperintensity volume (adjusted for hypertension)	4e-6
GCST011953_4	White matter hyperintensity volume x hypertension interaction (2df)	6e-6

EFO canonical traits (from GWAS)

8 canonical traits:

EFO ID	Trait name
EFO:0004842	eosinophil count
EFO:0005090	basophil count
EFO:0005091	monocyte count
EFO:0004312	vital capacity
EFO:0004314	forced expiratory volume
EFO:0006781	coffee consumption measurement
EFO:0005665	white matter hyperintensity measurement
EFO:0004527	mean corpuscular hemoglobin

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (7): CHEMBL3430886 (PROTEIN-PROTEIN INTERACTION), CHEMBL3430887 (PROTEIN-PROTEIN INTERACTION), CHEMBL3885515 (PROTEIN-PROTEIN INTERACTION), CHEMBL3885523 (PROTEIN COMPLEX), CHEMBL4361 (SINGLE PROTEIN), CHEMBL4523712 (PROTEIN-PROTEIN INTERACTION), CHEMBL6066576 (PROTEIN COMPLEX)

Drugs by curated mechanism of action (ChEMBL)

Drugs whose curated ChEMBL mechanism of action targets the MCL1 protein itself — single-protein targets only (drugs acting on a protein family or complex that merely includes it are excluded). Includes antibodies and oligonucleotides that bioactivity screening does not capture.

1 curated-mechanism drugs:

Drug	Modality	Max phase
OBATOCLAX MESYLATE	Small molecule	3

Molecules with ChEMBL bioactivity

Phase ≥1, by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 406,062 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

19 molecules by phase:

Molecule	Name	Phase	Patents
CHEMBL3187985	APOMORPHINE HYDROCHLORIDE	4	5,317
CHEMBL290106	BITHIONOL	4	6,490
CHEMBL6466	COUMARIN	4	204,529
CHEMBL496	HEXACHLOROPHENE	4	26,440
CHEMBL1201119	LIOTHYRONINE SODIUM	4	3,084
CHEMBL1200938	METHYSERGIDE MALEATE	4	4
CHEMBL1503	OMEPRAZOLE	4	52,666
CHEMBL728	PROCHLORPERAZINE	4	26,071
CHEMBL3137309	VENETOCLAX	4	9,905
CHEMBL408194	OBATOCLAX	3	3,066
CHEMBL297453	EPIGALOCATECHIN GALLATE	3	23,201
CHEMBL51483	GOSSYPOL	3	14,167
CHEMBL443684	NAVITOCLAX	3	5,008
CHEMBL12208	HYMECROMONE	2	18,551
CHEMBL6033457	ABBV-467	1	8
CHEMBL376408	ABT 737	1	4,433
CHEMBL4297482	AZD-5991	1	995
CHEMBL4650225	MURIZATOCLAX	1	560
CHEMBL4446378	TAPOTOCLAX	1	1,567

PharmGKB: 1 entry (CPIC guideline: no)

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: other protein — B-cell lymphoma 2 (Bcl-2) protein family

Most potent curated ligand interactions (3 total), top 3:

Ligand	Action	Affinity	Parameter
AZD5991	Antagonist	9.7	pKi
venetoclax	Antagonist	6.35	pKi
obatoclax	Antagonist	5.54	pKi

Binding affinities (BindingDB)

4798 measured of 5929 human assays (6100 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
(11R,20R)-23,26-dichloro-14-[[2-[6-[[(2S)-1,4-dioxan-2-yl]methylamino]-3-pyridinyl]pyrimidin-4-yl]methoxy]-3-(4-fluorophenyl)-24,25-dimethyl-20-[(4-methylpiperazin-1-yl)methyl]-10,18,21-trioxa-4-thia-6,8-diazapentacyclo[20.2.2.12,5.113,17.09,28]octacosa-1(25),2,5,7,9(28),13,15,17(27),22(26),23-decaene-11-carboxylic acid	KI	0.001 nM	US-10676485: Macrocyclic MCL-1 inhibitors and methods of use
MLS000068778	EC50	0.00197 nM
(11R,20R)-23,26-dichloro-14-[[2-[[(2R)-1,4-dioxan-2-yl]methoxy]pyrimidin-4-yl]methoxy]-3-(4-fluorophenyl)-24,25-dimethyl-20-[(4-methylpiperazin-1-yl)methyl]-10,18,21-trioxa-4-thia-6,8-diazapentacyclo[20.2.2.12,5.113,17.09,28]octacosa-1(25),2,5,7,9(28),13,15,17(27),22(26),23-decaene-11-carboxylic acid	KI	0.003 nM	US-10676485: Macrocyclic MCL-1 inhibitors and methods of use
(11R,20R)-23,26-dichloro-14-[[2-[4-[[(2R)-1,4-dioxan-2-yl]methoxymethyl]-4-fluorocyclohexyl]pyrimidin-4-yl]methoxy]-3-(4-fluorophenyl)-24,25-dimethyl-20-[(4-methylpiperazin-1-yl)methyl]-10,18,21-trioxa-4-thia-6,8-diazapentacyclo[20.2.2.12,5.113,17.09,28]octacosa-1(25),2,5,7,9(28),13,15,17(27),22(26),23-decaene-11-carboxylic acid	KI	0.004 nM	US-10676485: Macrocyclic MCL-1 inhibitors and methods of use
(11R,20R)-23,26-dichloro-14-[[2-[4-[[(2R)-1,4-dioxan-2-yl]methoxy]cyclohexyl]pyrimidin-4-yl]methoxy]-3-(4-fluorophenyl)-24,25-dimethyl-20-[(4-methylpiperazin-1-yl)methyl]-10,18,21-trioxa-4-thia-6,8-diazapentacyclo[20.2.2.12,5.113,17.09,28]octacosa-1(25),2,5,7,9(28),13,15,17(27),22(26),23-decaene-11-carboxylic acid	KI	0.005 nM	US-10676485: Macrocyclic MCL-1 inhibitors and methods of use
(11R,20R)-23,26-dichloro-14-[[2-[4-(1,3-dioxolan-4-ylmethoxy)cyclohexyl]pyrimidin-4-yl]methoxy]-3-(4-fluorophenyl)-24,25-dimethyl-20-[(4-methylpiperazin-1-yl)methyl]-10,18,21-trioxa-4-thia-6,8-diazapentacyclo[20.2.2.12,5.113,17.09,28]octacosa-1(25),2,5,7,9(28),13,15,17(27),22(26),23-decaene-11-carboxylic acid	KI	0.006 nM	US-10676485: Macrocyclic MCL-1 inhibitors and methods of use
CHEMBL5186095	KI	0.006 nM
(11R,20R)-23,26-dichloro-3-(2,3-dihydro-1,4-dioxin-5-yl)-14-[[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy]-24,25-dimethyl-20-[(4-methylpiperazin-1-yl)methyl]-10,18,21-trioxa-4-thia-6,8-diazapentacyclo[20.2.2.12,5.113,17.09,28]octacosa-1(25),2,5,7,9(28),13,15,17(27),22(26),23-decaene-11-carboxylic acid	KI	0.008 nM	US-10676485: Macrocyclic MCL-1 inhibitors and methods of use
(11R,20R)-23,26-dichloro-14-[[2-[6-[[(2R)-1,4-dioxan-2-yl]methylamino]-3-pyridinyl]pyrimidin-4-yl]methoxy]-3-(4-fluorophenyl)-24,25-dimethyl-20-[(4-methylpiperazin-1-yl)methyl]-10,18,21-trioxa-4-thia-6,8-diazapentacyclo[20.2.2.12,5.113,17.09,28]octacosa-1(25),2,5,7,9(28),13,15,17(27),22(26),23-decaene-11-carboxylic acid	KI	0.009 nM	US-10676485: Macrocyclic MCL-1 inhibitors and methods of use
trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-methoxycyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide	KI	0.01 nM	US-10213433
CHEMBL4444429	KI	0.01 nM
CHEMBL6168862	KI	0.01 nM
(11R,20R)-23,26-dichloro-14-[[2-[3-[[(2R)-1,4-dioxan-2-yl]methoxy]phenyl]pyrimidin-4-yl]methoxy]-3-(4-fluorophenyl)-24,25-dimethyl-20-[(4-methylpiperazin-1-yl)methyl]-10,18,21-trioxa-4-thia-6,8-diazapentacyclo[20.2.2.12,5.113,17.09,28]octacosa-1(25),2,5,7,9(28),13,15,17(27),22(26),23-decaene-11-carboxylic acid	KI	0.011 nM	US-10676485: Macrocyclic MCL-1 inhibitors and methods of use
(11R,20R)-23,26-dichloro-3-cyclobutyl-14-[[2-[4-(1,4-dioxan-2-ylmethoxy)cyclohexyl]pyrimidin-4-yl]methoxy]-24,25-dimethyl-20-[(4-methylpiperazin-1-yl)methyl]-10,18,21-trioxa-4-thia-6,8-diazapentacyclo[20.2.2.12,5.113,17.09,28]octacosa-1(25),2,5,7,9(28),13,15,17(27),22(26),23-decaene-11-carboxylic acid	KI	0.011 nM	US-10676485: Macrocyclic MCL-1 inhibitors and methods of use
(11R,20R)-23,26-dichloro-14-[[2-[(4S)-4-[[(2S)-1,4-dioxan-2-yl]methoxymethyl]-4-fluorocyclohexen-1-yl]pyrimidin-4-yl]methoxy]-3-(4-fluorophenyl)-24,25-dimethyl-20-[(4-methylpiperazin-1-yl)methyl]-10,18,21-trioxa-4-thia-6,8-diazapentacyclo[20.2.2.12,5.113,17.09,28]octacosa-1(25),2,5,7,9(28),13,15,17(27),22(26),23-decaene-11-carboxylic acid	KI	0.012 nM	US-10676485: Macrocyclic MCL-1 inhibitors and methods of use
(11R,20R)-23,26-dichloro-14-[[2-[4-(1,4-dioxan-2-ylmethoxy)cyclohexyl]pyrimidin-4-yl]methoxy]-3-(4-fluorophenyl)-24,25-dimethyl-20-[(4-methylpiperazin-1-yl)methyl]-10,18,21-trioxa-4-thia-6,8-diazapentacyclo[20.2.2.12,5.113,17.09,28]octacosa-1(25),2,5,7,9(28),13,15,17(27),22(26),23-decaene-11-carboxylic acid	KI	0.013 nM	US-10676485: Macrocyclic MCL-1 inhibitors and methods of use
(11R,20R)-23,26-dichloro-14-[[2-[4-[[(2R)-1,4-dioxan-2-yl]methoxymethyl]-4-fluorocyclohexyl]pyrimidin-4-yl]methoxy]-3-(4-fluorophenyl)-24,25-dimethyl-20-[(4-methylpiperazin-1-yl)methyl]-10,18,21-trioxa-4-thia-6,8-diazapentacyclo[20.2.2.12,5.113,17.09,28]octacosa-1(25),2,5,7,9(28),13,15,17(27),22(26),23-decaene-11-carboxylic acid	KI	0.013 nM	US-10676485: Macrocyclic MCL-1 inhibitors and methods of use
CHEMBL5396628	KI	0.013 nM
(11R,20R)-23,26-dichloro-14-[[2-[(4S)-4-[[(2R)-1,4-dioxan-2-yl]methoxymethyl]-4-fluorocyclohexen-1-yl]pyrimidin-4-yl]methoxy]-3-(4-fluorophenyl)-24,25-dimethyl-20-[(4-methylpiperazin-1-yl)methyl]-10,18,21-trioxa-4-thia-6,8-diazapentacyclo[20.2.2.12,5.113,17.09,28]octacosa-1(25),2,5,7,9(28),13,15,17(27),22(26),23-decaene-11-carboxylic acid	KI	0.014 nM	US-10676485: Macrocyclic MCL-1 inhibitors and methods of use
(11R,20R)-23,26-dichloro-14-[[2-(1,4-dioxepan-6-yl)pyrimidin-4-yl]methoxy]-3-(4-fluorophenyl)-24,25-dimethyl-20-[(4-methylpiperazin-1-yl)methyl]-10,18,21-trioxa-4-thia-6,8-diazapentacyclo[20.2.2.12,5.113,17.09,28]octacosa-1(25),2,5,7,9(28),13,15,17(27),22(26),23-decaene-11-carboxylic acid	KI	0.015 nM	US-10676485: Macrocyclic MCL-1 inhibitors and methods of use
CHEMBL5307201	KI	0.015 nM
N-[(3’R,4S,6’R,7’S,8’E,11’S)-7-chloro-7’-methoxy-11’-methyl-13’,15’-dioxospiro[2,3-dihydro-1H-naphthalene-4,22’-20-oxa-13lambda6-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,13,16(25),17,19(24)-pentaene]-13’-yl]-3-cyanoazetidine-1-carboxamide	IC50	0.016 nM	US-10703733: MCL-1 inhibitors
N-[(3’R,4S,6’R,7’S,10’S,11’S)-7-chloro-10’-hydroxy-7’-methoxy-11’-methyl-13’,15’-dioxospiro[2,3-dihydro-1H-naphthalene-4,22’-20-oxa-13lambda6-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-13,16(25),17,19(24)-tetraene]-13’-yl]-3-methoxy-1-methylpyrazole-4-carboxamide	IC50	0.016 nM	US-10703733: MCL-1 inhibitors
(11R,20R)-23,26-dichloro-14-[[2-[3-[[(2S)-1,4-dioxan-2-yl]methoxy]phenyl]pyrimidin-4-yl]methoxy]-3-(4-fluorophenyl)-24,25-dimethyl-20-[(4-methylpiperazin-1-yl)methyl]-10,18,21-trioxa-4-thia-6,8-diazapentacyclo[20.2.2.12,5.113,17.09,28]octacosa-1(25),2,5,7,9(28),13,15,17(27),22(26),23-decaene-11-carboxylic acid	KI	0.016 nM	US-10676485: Macrocyclic MCL-1 inhibitors and methods of use
(11R,20R)-23,26-dichloro-14-[[2-[4-[[(2S)-1,4-dioxan-2-yl]methoxymethyl]-4-fluorocyclohexyl]pyrimidin-4-yl]methoxy]-3-(4-fluorophenyl)-24,25-dimethyl-20-[(4-methylpiperazin-1-yl)methyl]-10,18,21-trioxa-4-thia-6,8-diazapentacyclo[20.2.2.12,5.113,17.09,28]octacosa-1(25),2,5,7,9(28),13,15,17(27),22(26),23-decaene-11-carboxylic acid	KI	0.017 nM	US-10676485: Macrocyclic MCL-1 inhibitors and methods of use
N-[(3’R,4S,6’R,7’S,11’S)-7-chloro-7’-methoxy-11’-methyl-13’,15’-dioxospiro[2,3-dihydro-1H-naphthalene-4,22’-20-oxa-13lambda6-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-13,16(25),17,19(24)-tetraene]-13’-yl]-3-methoxy-1-methylpyrazole-4-carboxamide	IC50	0.018 nM	US-10703733: MCL-1 inhibitors
N-[(3’R,4S,6’R,7’S,8’E,11’S)-7-chloro-7’-methoxy-11’-methyl-13’,15’-dioxospiro[2,3-dihydro-1H-naphthalene-4,22’-20-oxa-13lambda6-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,13,16(25),17,19(24)-pentaene]-13’-yl]-7-methyl-6-oxo-5-oxa-2,7-diazaspiro[3.4]octane-2-carboxamide	IC50	0.018 nM	US-10703733: MCL-1 inhibitors
(11R,20R)-23,26-dichloro-14-[[2-[(4R)-4-[[(2S)-1,4-dioxan-2-yl]methoxymethyl]-4-fluorocyclohexen-1-yl]pyrimidin-4-yl]methoxy]-3-(4-fluorophenyl)-24,25-dimethyl-20-[(4-methylpiperazin-1-yl)methyl]-10,18,21-trioxa-4-thia-6,8-diazapentacyclo[20.2.2.12,5.113,17.09,28]octacosa-1(25),2,5,7,9(28),13,15,17(27),22(26),23-decaene-11-carboxylic acid	KI	0.018 nM	US-10676485: Macrocyclic MCL-1 inhibitors and methods of use
CHEMBL5400376	KI	0.018 nM
[(1S)-1-[(1R,2R)-2-[[(4S)-7-chloro-7’-[[[(2R,3S)-3-methylhex-5-en-2-yl]-oxo-[(2,2,2-trifluoroacetyl)amino]-lambda6-sulfanylidene]carbamoyl]spiro[2,3-dihydro-1H-naphthalene-4,3’-2,4-dihydro-1,5-benzoxazepine]-5’-yl]methyl]cyclobutyl]prop-2-enyl] acetate	IC50	0.019 nM	US-10703733: MCL-1 inhibitors
[1-[[(3’R,4S,6’R,7’S,8’E,11’S)-7-chloro-7’-methoxy-11’-methyl-13’,15’-dioxospiro[2,3-dihydro-1H-naphthalene-4,22’-20-oxa-13lambda6-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,13,16(25),17,19(24)-pentaene]-13’-yl]carbamoyl]azetidin-3-yl] N,N-dimethylcarbamate	IC50	0.02 nM	US-10703733: MCL-1 inhibitors
(11R,20R)-23,26-dichloro-14-[[2-[(4R)-4-[[(2R)-1,4-dioxan-2-yl]methoxymethyl]-4-fluorocyclohexen-1-yl]pyrimidin-4-yl]methoxy]-3-(4-fluorophenyl)-24,25-dimethyl-20-[(4-methylpiperazin-1-yl)methyl]-10,18,21-trioxa-4-thia-6,8-diazapentacyclo[20.2.2.12,5.113,17.09,28]octacosa-1(25),2,5,7,9(28),13,15,17(27),22(26),23-decaene-11-carboxylic acid	KI	0.02 nM	US-10676485: Macrocyclic MCL-1 inhibitors and methods of use
(11R,20R)-23,26-dichloro-14-[[2-[4-[[(2S)-1,4-dioxan-2-yl]methoxy]cyclohexyl]pyrimidin-4-yl]methoxy]-3-(4-fluorophenyl)-24,25-dimethyl-20-[(4-methylpiperazin-1-yl)methyl]-10,18,21-trioxa-4-thia-6,8-diazapentacyclo[20.2.2.12,5.113,17.09,28]octacosa-1(25),2,5,7,9(28),13,15,17(27),22(26),23-decaene-11-carboxylic acid	KI	0.02 nM	US-10676485: Macrocyclic MCL-1 inhibitors and methods of use
[1-[[(3’R,4S,6’R,7’S,8’E,11’S)-7-chloro-7’-hydroxy-11’-methyl-13’,15’-dioxospiro[2,3-dihydro-1H-naphthalene-4,22’-20-oxa-13lambda6-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,13,16(25),17,19(24)-pentaene]-13’-yl]carbamoyl]azetidin-3-yl] N,N-dimethylcarbamate	IC50	0.02 nM	US-10988451: MCL-1 inhibitors
CHEMBL5402764	KI	0.02 nM
CHEMBL5426737	KI	0.02 nM
1-[(3’R,4S,6’R,7’S,8’E,11’S)-7-chloro-7’-methoxy-11’-methyl-13’,15’-dioxospiro[2,3-dihydro-1H-naphthalene-4,22’-20-oxa-13lambda6-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,13,16(25),17,19(24)-pentaene]-13’-yl]-3-(3-hydroxy-3-methylcyclobutyl)urea	IC50	0.022 nM	US-10703733: MCL-1 inhibitors
(11R,20R)-23,26-dichloro-3-(cyclopenten-1-yl)-14-[[2-[4-(1,4-dioxan-2-ylmethoxy)cyclohexyl]pyrimidin-4-yl]methoxy]-24,25-dimethyl-20-[(4-methylpiperazin-1-yl)methyl]-10,18,21-trioxa-4-thia-6,8-diazapentacyclo[20.2.2.12,5.113,17.09,28]octacosa-1(25),2,5,7,9(28),13,15,17(27),22(26),23-decaene-11-carboxylic acid	KI	0.022 nM	US-10676485: Macrocyclic MCL-1 inhibitors and methods of use
(11R,20R)-23,26-dichloro-14-[[2-[4-[[(2S)-1,4-dioxan-2-yl]methoxymethyl]-4-fluorocyclohexyl]pyrimidin-4-yl]methoxy]-3-(4-fluorophenyl)-24,25-dimethyl-20-[(4-methylpiperazin-1-yl)methyl]-10,18,21-trioxa-4-thia-6,8-diazapentacyclo[20.2.2.12,5.113,17.09,28]octacosa-1(25),2,5,7,9(28),13,15,17(27),22(26),23-decaene-11-carboxylic acid	KI	0.022 nM	US-10676485: Macrocyclic MCL-1 inhibitors and methods of use
(11R,20R)-23,26-dichloro-14-[[2-[4-[[(2S)-1,4-dioxan-2-yl]methoxymethyl]cyclohexyl]pyrimidin-4-yl]methoxy]-3-(4-fluorophenyl)-24,25-dimethyl-20-[(4-methylpiperazin-1-yl)methyl]-10,18,21-trioxa-4-thia-6,8-diazapentacyclo[20.2.2.12,5.113,17.09,28]octacosa-1(25),2,5,7,9(28),13,15,17(27),22(26),23-decaene-11-carboxylic acid	KI	0.022 nM	US-10676485: Macrocyclic MCL-1 inhibitors and methods of use
CHEMBL5437853	KI	0.022 nM
(11R,20R)-23,26-dichloro-3-(cyclopenten-1-yl)-14-[[2-[4-[[(2S)-1,4-dioxan-2-yl]methoxymethyl]-4-fluorocyclohexyl]pyrimidin-4-yl]methoxy]-24,25-dimethyl-20-[(4-methylpiperazin-1-yl)methyl]-10,18,21-trioxa-4-thia-6,8-diazapentacyclo[20.2.2.12,5.113,17.09,28]octacosa-1(25),2,5,7,9(28),13,15,17(27),22(26),23-decaene-11-carboxylic acid	KI	0.023 nM	US-10676485: Macrocyclic MCL-1 inhibitors and methods of use
CHEMBL5412641	KI	0.023 nM
1-[(3’R,4S,6’R,7’S,8’E,11’S)-7-chloro-7’-methoxy-11’-methyl-13’,15’-dioxospiro[2,3-dihydro-1H-naphthalene-4,22’-20-oxa-13lambda6-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,13,16(25),17,19(24)-pentaene]-13’-yl]-3-[(1S,2S)-2-(difluoromethyl)cyclopropyl]urea	IC50	0.024 nM	US-10703733: MCL-1 inhibitors
N-[(3’R,4S,6’R,7’S,8’E,11’S)-7-chloro-7’-methoxy-11’-methyl-13’,15’-dioxospiro[2,3-dihydro-1H-naphthalene-4,22’-20-oxa-13lambda6-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,13,16(25),17,19(24)-pentaene]-13’-yl]-3-methoxyazetidine-1-carboxamide	IC50	0.024 nM	US-10703733: MCL-1 inhibitors
1-[(3’R,4S,6’R,7’S,8’E,11’S)-7-chloro-7’-methoxy-11’-methyl-13’,15’-dioxospiro[2,3-dihydro-1H-naphthalene-4,22’-20-oxa-13lambda6-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,13,16(25),17,19(24)-pentaene]-13’-yl]-3-[(1S)-2,2-difluorocyclopropyl]urea	IC50	0.025 nM	US-10703733: MCL-1 inhibitors
[(3’R,4S,6’R,7’S,8’E,11’S)-7-chloro-13’-[(3-methoxy-1-methylpyrazole-4-carbonyl)amino]-11’-methyl-13’,15’-dioxospiro[2,3-dihydro-1H-naphthalene-4,22’-20-oxa-13lambda6-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,13,16(25),17,19(24)-pentaene]-7’-yl] 3-morpholin-4-ylpropanoate	IC50	0.026 nM	US-10703733: MCL-1 inhibitors
N-[(3’R,4S,6’R,7’S,8’E,11’S)-7-chloro-7’-methoxy-11’-methyl-13’,15’-dioxospiro[2,3-dihydro-1H-naphthalene-4,22’-20-oxa-13lambda6-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,13,16(25),17,19(24)-pentaene]-13’-yl]-3-morpholin-4-ylazetidine-1-carboxamide	IC50	0.026 nM	US-10703733: MCL-1 inhibitors
(11R,20R)-23,26-dichloro-3-(cyclopenten-1-yl)-14-[[2-[(4R)-4-[[(2R)-1,4-dioxan-2-yl]methoxymethyl]-4-fluorocyclohexen-1-yl]pyrimidin-4-yl]methoxy]-24,25-dimethyl-20-[(4-methylpiperazin-1-yl)methyl]-10,18,21-trioxa-4-thia-6,8-diazapentacyclo[20.2.2.12,5.113,17.09,28]octacosa-1(25),2,5,7,9(28),13,15,17(27),22(26),23-decaene-11-carboxylic acid	KI	0.026 nM	US-10676485: Macrocyclic MCL-1 inhibitors and methods of use
(3’R,4S,6’R,7’R,8’E,11’S,12’R)-7-chloro-7’-hydroxy-11’,12’-dimethyl-7’-[3-(oxan-4-yl)prop-1-ynyl]-13’,13’-dioxospiro[2,3-dihydro-1H-naphthalene-4,22’-20-oxa-13lambda6-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16(25),17,19(24)-tetraene]-15’-one	IC50	0.026 nM	US-11224601: Compounds that inhibits MCL-1 protein

ChEMBL bioactivities

6100 potent at pChembl≥5 of 6100 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
11.00	Ki	0.01	nM	CHEMBL6168862
10.96	Ki	0.011	nM	CHEMBL5799571
10.96	Ki	0.011	nM	CHEMBL5768839
10.96	IC50	0.011	nM	CHEMBL5885338
10.92	Ki	0.012	nM	MURIZATOCLAX
10.92	Ki	0.012	nM	CHEMBL5775900
10.89	Ki	0.013	nM	CHEMBL5396628
10.89	Ki	0.013	nM	CHEMBL5809179
10.89	Ki	0.013	nM	CHEMBL5902520
10.85	Ki	0.014	nM	CHEMBL5181717
10.85	Ki	0.014	nM	CHEMBL5845523
10.85	Ki	0.014	nM	CHEMBL5949336
10.82	Ki	0.015	nM	CHEMBL5307562
10.82	Ki	0.015	nM	CHEMBL5307201
10.82	Ki	0.015	nM	MURIZATOCLAX
10.82	Ki	0.015	nM	CHEMBL5792786
10.82	Ki	0.015	nM	CHEMBL6170290
10.82	IC50	0.015	nM	CHEMBL6170290
10.80	IC50	0.016	nM	CHEMBL5891096
10.80	IC50	0.016	nM	CHEMBL5907521
10.80	Ki	0.016	nM	CHEMBL5897821
10.80	IC50	0.016	nM	CHEMBL6022456
10.77	Ki	0.017	nM	CHEMBL5949309
10.74	Ki	0.018	nM	CHEMBL5400376
10.74	IC50	0.018	nM	CHEMBL5849267
10.74	IC50	0.018	nM	CHEMBL6014845
10.74	Ki	0.018	nM	CHEMBL5960151
10.74	IC50	0.018	nM	CHEMBL5924042
10.72	IC50	0.019	nM	CHEMBL5950527
10.72	IC50	0.019	nM	CHEMBL6045884
10.70	Ki	0.02	nM	CHEMBL5402764
10.70	Ki	0.02	nM	CHEMBL5426737
10.70	IC50	0.02	nM	CHEMBL5749525
10.70	Ki	0.02	nM	CHEMBL5813465
10.70	Ki	0.02	nM	CHEMBL5837883
10.70	Ki	0.02	nM	CHEMBL6022463
10.70	IC50	0.02	nM	CHEMBL5852367
10.68	Ki	0.021	nM	CHEMBL5890121
10.66	Ki	0.022	nM	CHEMBL5437853
10.66	IC50	0.022	nM	CHEMBL5817494
10.66	Ki	0.022	nM	CHEMBL5748363
10.66	Ki	0.022	nM	CHEMBL5768089
10.66	Ki	0.022	nM	CHEMBL5978854
10.64	Ki	0.023	nM	CHEMBL5412641
10.64	Ki	0.023	nM	CHEMBL5977386
10.62	IC50	0.024	nM	CHEMBL5878551
10.62	IC50	0.024	nM	CHEMBL5968615
10.60	IC50	0.025	nM	CHEMBL5778497
10.59	Ki	0.026	nM	CHEMBL5538127
10.59	IC50	0.026	nM	CHEMBL5906689

PubChem BioAssay actives

1996 with measured affinity, of 3214 total; 50 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
(2R)-2-[5-[3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl]-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy-3-[2-[[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy]phenyl]propanoic acid	2121329: Binding affinity to MCL-1 (unknown origin) by quench assay	ki	<0.0001	uM
(3’R,4S,6’R,7’S,8’E,12’R)-7-chloro-7’-hydroxy-12’-methyl-13’,13’-dioxospiro[2,3-dihydro-1H-naphthalene-4,22’-20-oxa-13lambda6-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16(25),17,19(24)-tetraene]-15’-one	1580110: Inhibition of TAMRA-labeled BIM BH3 peptide binding to human Mcl1 (171 to 327 residues) incubated for 120 mins by fluorescence polarization	ki	<0.0001	uM
17-chloro-5,13,14,22-tetramethyl-28-oxa-2,9-dithia-5,6,12,13,22-pentazaheptacyclo[27.7.1.14,7.011,15.016,21.020,24.030,35]octatriaconta-1(36),4(38),6,11,14,16,18,20,23,29(37),30,32,34-tridecaene-23-carboxylic acid	2070075: Binding affinity to human Mcl-1 assessed as inhibition constant	ki	<0.0001	uM
3-[(4R)-7-chloro-10-[3-(4-chloro-3,5-dimethylphenoxy)propyl]-4-methyl-1-oxo-6-(1,3,5-trimethylpyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2-yl]-1-methylindole-5-carboxylic acid	1587374: Inhibition of FITC-labeled Bak peptide binding to MBP-fused Mcl-1 (unknown origin) measured after 3 hrs by TR-FRET assay	ki	<0.0001	uM
7-[3-[(1,5-dimethylpyrazol-3-yl)methylsulfanylmethyl]-1,5-dimethylpyrazol-4-yl]-3-(3-naphthalen-1-yloxypropyl)-1H-indole-2-carboxylic acid	1845346: Inhibition of N-terminal GST-tagged Mcl-1 (171 to 327 residues) (unknown origin) expressed in Escherichia coli using fluor 647-labeled Bim peptide WIAQELRRIGDEFN as substrate incubated for 120 to 180 mins by TR-FRET assay	ic50	<0.0001	uM
(11R,20R)-23,26-dichloro-14-[[2-[4-[[(2S)-1,4-dioxan-2-yl]methoxy]phenyl]pyrimidin-4-yl]methoxy]-3-(4-fluorophenyl)-24,25-dimethyl-20-[(4-methylpiperazin-1-yl)methyl]-10,18,21-trioxa-4-thia-6,8-diazapentacyclo[20.2.2.12,5.113,17.09,28]octacosa-1(25),2,5,7,9(28),13,15,17(27),22(26),23-decaene-11-carboxylic acid	2070094: Binding affinity to Mcl-1 (unknown origin) assessed as inhibition constant	ki	<0.0001	uM
(2S)-2-[5-[3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl]-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy-3-[2-[[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy]phenyl]propanoic acid	2070084: Binding affinity to Mcl-1 (unknown origin) assessed as inhibition constant by Fluorescence polarization assay	ki	<0.0001	uM
2-[(3’R,4S,6’R,7’S,8’E,11’S,12’R)-7-chloro-7’-hydroxy-11’,12’-dimethyl-13’,13’,15’-trioxospiro[2,3-dihydro-1H-naphthalene-4,22’-20-oxa-13lambda6-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16(25),17,19(24)-tetraene]-7’-yl]-N,N-dimethylacetamide	1845330: Inhibition of recombinant His6-tagged human MCL1 (171 to 327 residues) expressed in Escherichia coli and biotinylated Bim BH3 peptide interaction using Biotin-DMRPEIWIAQELRRIGDEFNAYYARR as substrate incubated for 60 mins by TR-FRET analysis	ki	<0.0001	uM
2-[(3’R,4S,6’R,7’S,8’E,11’S,12’R)-7-chloro-7’-methoxy-11’,12’-dimethyl-13’,13’,15’-trioxospiro[2,3-dihydro-1H-naphthalene-4,22’-20-oxa-13lambda6-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16(25),17,19(24)-tetraene]-7’-yl]-N,N-dimethylacetamide	1845330: Inhibition of recombinant His6-tagged human MCL1 (171 to 327 residues) expressed in Escherichia coli and biotinylated Bim BH3 peptide interaction using Biotin-DMRPEIWIAQELRRIGDEFNAYYARR as substrate incubated for 60 mins by TR-FRET analysis	ki	<0.0001	uM
(3’R,4S,6’R,7’R,8’E,11’S,12’R)-7’-[[(9aR)-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl]methyl]-7-chloro-7’-methoxy-11’,12’-dimethyl-13’,13’-dioxospiro[2,3-dihydro-1H-naphthalene-4,22’-20-oxa-13lambda6-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16(25),17,19(24)-tetraene]-15’-one	1845330: Inhibition of recombinant His6-tagged human MCL1 (171 to 327 residues) expressed in Escherichia coli and biotinylated Bim BH3 peptide interaction using Biotin-DMRPEIWIAQELRRIGDEFNAYYARR as substrate incubated for 60 mins by TR-FRET analysis	ki	<0.0001	uM
(3’R,4S,6’R,7’S,8’E,11’S,12’R)-7’-[[(9aR)-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl]methyl]-7-chloro-7’-methoxy-11’,12’-dimethyl-13’,13’-dioxospiro[2,3-dihydro-1H-naphthalene-4,22’-20-oxa-13lambda6-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16(25),17,19(24)-tetraene]-15’-one	2231799: Binding affinity to MCL-1 (unknown origin) assessed as inhibition constant by TR-FRET assay	ki	<0.0001	uM
N-[(3’R,4S,6’R,7’S,8’E,11’S)-7-chloro-7’-methoxy-11’-methyl-13’,15’-dioxospiro[2,3-dihydro-1H-naphthalene-4,22’-20-oxa-13lambda6-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,13,16(25),17,19(24)-pentaene]-13’-yl]-1-methyl-5-[[4-(oxetan-3-yl)piperazin-1-yl]methyl]pyrrole-3-carboxamide	1845337: Inhibition of C-terminal His6-tagged recombinant human MCL-1 (171 to 327 residues/biotinylated Bim (51 to 76 residues) interaction incubated for 1 hrs followed by Bim addition and measured after 2 hrs by AlphaLISA assay	ic50	<0.0001	uM
17-chloro-5,12,14,22-tetramethyl-28-oxa-2,9-dithia-5,6,13,14,22-pentazaheptacyclo[27.7.1.14,7.011,15.016,21.020,24.030,35]octatriaconta-1(36),4(38),6,11(15),12,16,18,20,23,29(37),30,32,34-tridecaene-23-carboxylic acid	2010172: Displacement of Cy5-labeled BIM BH3 peptide (H3N-(C/Cy5Mal)-WIAQELRRIGDEFN-OH) from MCL-1 (unknown origin) assessed as inhibition constant incubated for 60 mins by HTRF assay	ki	<0.0001	uM
(3’R,4S,6’R,7’S,8’E,15’R)-7-chloro-7’-[2-(dimethylamino)-2-oxoethoxy]-N-(dimethylsulfamoyl)-15’-hydroxy-12’-methyl-13’-oxospiro[2,3-dihydro-1H-naphthalene-4,22’-20-oxa-1,12-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16(25),17,19(24)-tetraene]-15’-carboxamide	1558895: Inhibition of recombinant C-terminal His6x-tagged human Mcl-1 (171 to 327 residues) interaction with biotinylated human Bim (51 to 76 residues) incubated for 60 mins in presence of 5 nM biotin-Bim by HTRF assay	ki	<0.0001	uM
17-chloro-12-[2-(2-methoxyethoxy)ethyl]-5,14,22-trimethyl-28-oxa-9-thia-5,6,12,13,24-pentazaheptacyclo[27.7.1.14,7.011,15.016,21.020,24.030,35]octatriaconta-1(36),4(38),6,11(15),13,16,18,20,22,29(37),30,32,34-tridecaene-23-carboxylic acid	2070075: Binding affinity to human Mcl-1 assessed as inhibition constant	ki	<0.0001	uM
17-chloro-33-fluoro-12-[2-(2-methoxyethoxy)ethyl]-5,14,22-trimethyl-28-oxa-9-thia-5,6,12,13,24-pentazaheptacyclo[27.7.1.14,7.011,15.016,21.020,24.030,35]octatriaconta-1(36),4(38),6,11(15),13,16,18,20,22,29(37),30(35),31,33-tridecaene-23-carboxylic acid	2010172: Displacement of Cy5-labeled BIM BH3 peptide (H3N-(C/Cy5Mal)-WIAQELRRIGDEFN-OH) from MCL-1 (unknown origin) assessed as inhibition constant incubated for 60 mins by HTRF assay	ki	<0.0001	uM
2-[(3’R,4S,6’R,7’S,8’E,11’S,12’R)-7-chloro-11’,12’-dimethyl-13’,13’,15’-trioxospiro[2,3-dihydro-1H-naphthalene-4,22’-20-oxa-13lambda6-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16(25),17,19(24)-tetraene]-7’-yl]oxyacetic acid	1845330: Inhibition of recombinant His6-tagged human MCL1 (171 to 327 residues) expressed in Escherichia coli and biotinylated Bim BH3 peptide interaction using Biotin-DMRPEIWIAQELRRIGDEFNAYYARR as substrate incubated for 60 mins by TR-FRET analysis	ki	<0.0001	uM
17-chloro-12-(2-methoxyethoxymethyl)-5,14,22-trimethyl-28-oxa-9-thia-5,6,13,14,22-pentazaheptacyclo[27.7.1.14,7.011,15.016,21.020,24.030,35]octatriaconta-1(36),4(38),6,11(15),12,16,18,20,23,29(37),30,32,34-tridecaene-23-carboxylic acid	2010172: Displacement of Cy5-labeled BIM BH3 peptide (H3N-(C/Cy5Mal)-WIAQELRRIGDEFN-OH) from MCL-1 (unknown origin) assessed as inhibition constant incubated for 60 mins by HTRF assay	ki	<0.0001	uM
17-chloro-33-fluoro-22-(2-methoxyethyl)-5,14-dimethyl-28-oxa-9-thia-5,6,13,14,22-pentazaheptacyclo[27.7.1.14,7.011,15.016,21.020,24.030,35]octatriaconta-1(36),4(38),6,11(15),12,16,18,20,23,29(37),30(35),31,33-tridecaene-23-carboxylic acid	2010172: Displacement of Cy5-labeled BIM BH3 peptide (H3N-(C/Cy5Mal)-WIAQELRRIGDEFN-OH) from MCL-1 (unknown origin) assessed as inhibition constant incubated for 60 mins by HTRF assay	ki	<0.0001	uM
17-chloro-33-fluoro-22-[2-(2-methoxyethoxy)ethyl]-5,14-dimethyl-28-oxa-9-thia-5,6,13,14,22-pentazaheptacyclo[27.7.1.14,7.011,15.016,21.020,24.030,35]octatriaconta-1(36),4(38),6,11(15),12,16,18,20,23,29(37),30(35),31,33-tridecaene-23-carboxylic acid	2010172: Displacement of Cy5-labeled BIM BH3 peptide (H3N-(C/Cy5Mal)-WIAQELRRIGDEFN-OH) from MCL-1 (unknown origin) assessed as inhibition constant incubated for 60 mins by HTRF assay	ki	<0.0001	uM
17-chloro-33-fluoro-12-[2-(2-methoxyethoxy)ethyl]-5,14,22-trimethyl-28-oxa-9-thia-5,6,13,14,22-pentazaheptacyclo[27.7.1.14,7.011,15.016,21.020,24.030,35]octatriaconta-1(36),4(38),6,11(15),12,16,18,20,23,29(37),30(35),31,33-tridecaene-23-carboxylic acid	2010172: Displacement of Cy5-labeled BIM BH3 peptide (H3N-(C/Cy5Mal)-WIAQELRRIGDEFN-OH) from MCL-1 (unknown origin) assessed as inhibition constant incubated for 60 mins by HTRF assay	ki	<0.0001	uM
17-chloro-33-fluoro-5,14-dimethyl-22-(2-morpholin-4-ylethyl)-28-oxa-9-thia-5,6,13,14,22-pentazaheptacyclo[27.7.1.14,7.011,15.016,21.020,24.030,35]octatriaconta-1(36),4(38),6,11(15),12,16,18,20,23,29(37),30(35),31,33-tridecaene-23-carboxylic acid	2010172: Displacement of Cy5-labeled BIM BH3 peptide (H3N-(C/Cy5Mal)-WIAQELRRIGDEFN-OH) from MCL-1 (unknown origin) assessed as inhibition constant incubated for 60 mins by HTRF assay	ki	<0.0001	uM
17-chloro-33-fluoro-5,14-dimethyl-28-oxa-9-thia-5,6,13,14,22-pentazaheptacyclo[27.7.1.14,7.011,15.016,21.020,24.030,35]octatriaconta-1(36),4(38),6,11(15),12,16,18,20,23,29(37),30(35),31,33-tridecaene-23-carboxylic acid	2010172: Displacement of Cy5-labeled BIM BH3 peptide (H3N-(C/Cy5Mal)-WIAQELRRIGDEFN-OH) from MCL-1 (unknown origin) assessed as inhibition constant incubated for 60 mins by HTRF assay	ki	<0.0001	uM
17-chloro-22-[2-(dimethylamino)ethyl]-33-fluoro-5,14-dimethyl-28-oxa-9-thia-5,6,13,14,22-pentazaheptacyclo[27.7.1.14,7.011,15.016,21.020,24.030,35]octatriaconta-1(36),4(38),6,11(15),12,16,18,20,23,29(37),30(35),31,33-tridecaene-23-carboxylic acid	2010172: Displacement of Cy5-labeled BIM BH3 peptide (H3N-(C/Cy5Mal)-WIAQELRRIGDEFN-OH) from MCL-1 (unknown origin) assessed as inhibition constant incubated for 60 mins by HTRF assay	ki	<0.0001	uM
17-chloro-33-fluoro-12-(2-methoxyethoxymethyl)-5,14,22-trimethyl-28-oxa-9-thia-5,6,13,14,22-pentazaheptacyclo[27.7.1.14,7.011,15.016,21.020,24.030,35]octatriaconta-1(36),4(38),6,11(15),12,16,18,20,23,29(37),30(35),31,33-tridecaene-23-carboxylic acid	2010172: Displacement of Cy5-labeled BIM BH3 peptide (H3N-(C/Cy5Mal)-WIAQELRRIGDEFN-OH) from MCL-1 (unknown origin) assessed as inhibition constant incubated for 60 mins by HTRF assay	ki	<0.0001	uM
sodium 17-chloro-33-fluoro-5,12,14,22-tetramethyl-28-oxa-9-thia-5,6,13,14,22-pentazaheptacyclo[27.7.1.14,7.011,15.016,21.020,24.030,35]octatriaconta-1(36),4(38),6,11(15),12,16,18,20,23,29(37),30(35),31,33-tridecaene-23-carboxylate	2010172: Displacement of Cy5-labeled BIM BH3 peptide (H3N-(C/Cy5Mal)-WIAQELRRIGDEFN-OH) from MCL-1 (unknown origin) assessed as inhibition constant incubated for 60 mins by HTRF assay	ki	<0.0001	uM
sodium 17-chloro-5,12,14,22-tetramethyl-28-oxa-9-thia-5,6,13,14,22-pentazaheptacyclo[27.7.1.14,7.011,15.016,21.020,24.030,35]octatriaconta-1(36),4(38),6,11(15),12,16,18,20,23,29(37),30,32,34-tridecaene-23-carboxylate	2010172: Displacement of Cy5-labeled BIM BH3 peptide (H3N-(C/Cy5Mal)-WIAQELRRIGDEFN-OH) from MCL-1 (unknown origin) assessed as inhibition constant incubated for 60 mins by HTRF assay	ki	<0.0001	uM
(11R)-23,26-dichloro-14-[[2-[4-[[(2R)-1,4-dioxan-2-yl]methoxy]phenyl]pyrimidin-4-yl]methoxy]-3-(4-fluorophenyl)-24,25-dimethyl-20-[(4-methylpiperazin-1-yl)methyl]-10,18,21-trioxa-4-thia-6,8-diazapentacyclo[20.2.2.12,5.113,17.09,28]octacosa-1(25),2,5,7,9(28),13,15,17(27),22(26),23-decaene-11-carboxylic acid	2231799: Binding affinity to MCL-1 (unknown origin) assessed as inhibition constant by TR-FRET assay	ki	<0.0001	uM
(3’R,4S,6’R,7’S,8’E,12’R)-7-chloro-12’-ethyl-7’-hydroxy-13’,13’-dioxospiro[2,3-dihydro-1H-naphthalene-4,22’-20-oxa-13lambda6-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16(25),17,19(24)-tetraene]-15’-one	1580110: Inhibition of TAMRA-labeled BIM BH3 peptide binding to human Mcl1 (171 to 327 residues) incubated for 120 mins by fluorescence polarization	ki	0.0001	uM
(3’R,4S,6’R,7’S,8’E,11’S,12’R)-7-chloro-7’-hydroxy-11’,12’-dimethyl-13’,13’-dioxospiro[2,3-dihydro-1H-naphthalene-4,22’-20-oxa-13lambda6-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16(25),17,19(24)-tetraene]-15’-one	1558895: Inhibition of recombinant C-terminal His6x-tagged human Mcl-1 (171 to 327 residues) interaction with biotinylated human Bim (51 to 76 residues) incubated for 60 mins in presence of 5 nM biotin-Bim by HTRF assay	ki	0.0001	uM
(3’R,4S,6’R,7’S,12’R)-7-chloro-7’-hydroxy-12’-methyl-13’,13’-dioxospiro[2,3-dihydro-1H-naphthalene-4,22’-20-oxa-13lambda6-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-16(25),17,19(24)-triene]-15’-one	1580110: Inhibition of TAMRA-labeled BIM BH3 peptide binding to human Mcl1 (171 to 327 residues) incubated for 120 mins by fluorescence polarization	ki	0.0001	uM
(3’R,4S,6’R,7’S,8’E,11’S,12’R)-7-chloro-7’-methoxy-11’,12’-dimethyl-13’,13’-dioxospiro[2,3-dihydro-1H-naphthalene-4,22’-20-oxa-13lambda6-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16(25),17,19(24)-tetraene]-15’-one	1558895: Inhibition of recombinant C-terminal His6x-tagged human Mcl-1 (171 to 327 residues) interaction with biotinylated human Bim (51 to 76 residues) incubated for 60 mins in presence of 5 nM biotin-Bim by HTRF assay	ki	0.0001	uM
3-[8-chloro-11-[3-(4-chloro-3,5-dimethylphenoxy)propyl]-1-oxo-7-(1,3,5-trimethylpyrazol-4-yl)-4,5-dihydro-3H-[1,4]diazepino[1,2-a]indol-2-yl]-1-methylindole-5-carboxylic acid	1468272: Inhibition of FITC-Bak-BH3 binding to MBP-fused MCL1 (172 to 327 residues) (unknown origin) expressed in Escherichia coli BL21 CodonPlus (DE3) RIL after 3 hrs by TR-FRET assay	ki	0.0001	uM
(3’R,4S,6’R,7’S,8’E,15’R)-7-chloro-7’-[3-(3,3-difluoroazetidin-1-yl)propoxy]-N-(dimethylsulfamoyl)-15’-hydroxy-12’-methyl-13’-oxospiro[2,3-dihydro-1H-naphthalene-4,22’-20-oxa-1,12-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16(25),17,19(24)-tetraene]-15’-carboxamide	1558895: Inhibition of recombinant C-terminal His6x-tagged human Mcl-1 (171 to 327 residues) interaction with biotinylated human Bim (51 to 76 residues) incubated for 60 mins in presence of 5 nM biotin-Bim by HTRF assay	ki	0.0001	uM
7-[(4R)-7-chloro-10-[3-(4-chloro-3,5-dimethylphenoxy)propyl]-4-methyl-1-oxo-6-(1,3,5-trimethylpyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2-yl]-4-methoxy-1-methylindole-2-carboxylic acid	2113968: Binding affinity to His 6-fused Mcl-1 (unknown origin) expressed in Escherichia coli BL21 (DE3) assessed as inhibition constant incubated for 3 hrs by TR-FRET method	ki	0.0001	uM
3-[(4R)-7-chloro-10-[3-(4-chloro-3,5-dimethylphenoxy)propyl]-4-methyl-1-oxo-6-(1,3,5-trimethylpyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2-yl]-1-methylindole-6-carboxylic acid	1587374: Inhibition of FITC-labeled Bak peptide binding to MBP-fused Mcl-1 (unknown origin) measured after 3 hrs by TR-FRET assay	ki	0.0001	uM
7-[(4R)-7-chloro-10-[3-(4-chloro-3,5-dimethylphenoxy)propyl]-4-methyl-1-oxo-6-(1,3,5-trimethylpyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2-yl]-4,5-dimethoxy-1-methylindole-2-carboxylic acid	2113968: Binding affinity to His 6-fused Mcl-1 (unknown origin) expressed in Escherichia coli BL21 (DE3) assessed as inhibition constant incubated for 3 hrs by TR-FRET method	ki	0.0001	uM
(3’R,4S,6’R,7’S,11’S,12’R)-7-chloro-7’-[5-(dimethylamino)-1,3-dioxan-2-yl]-11’,12’-dimethyl-13’,13’-dioxospiro[2,3-dihydro-1H-naphthalene-4,22’-20-oxa-13lambda6-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-16(25),17,19(24)-triene]-15’-one	1845330: Inhibition of recombinant His6-tagged human MCL1 (171 to 327 residues) expressed in Escherichia coli and biotinylated Bim BH3 peptide interaction using Biotin-DMRPEIWIAQELRRIGDEFNAYYARR as substrate incubated for 60 mins by TR-FRET analysis	ki	0.0001	uM
(3’R,4S,6’R,7’S,8’E,15’R)-7-chloro-7’-[2-(3,3-difluoroazetidin-1-yl)ethoxy]-N-(dimethylsulfamoyl)-15’-hydroxy-12’-methyl-13’-oxospiro[2,3-dihydro-1H-naphthalene-4,22’-20-oxa-1,12-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16(25),17,19(24)-tetraene]-15’-carboxamide	1558895: Inhibition of recombinant C-terminal His6x-tagged human Mcl-1 (171 to 327 residues) interaction with biotinylated human Bim (51 to 76 residues) incubated for 60 mins in presence of 5 nM biotin-Bim by HTRF assay	ki	0.0001	uM
(3’R,4S,6’R,7’S,8’E,15’R)-7-chloro-N-(dimethylsulfamoyl)-15’-hydroxy-7’-methoxy-12’-methyl-13’-oxospiro[2,3-dihydro-1H-naphthalene-4,22’-20-oxa-1,12-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16(25),17,19(24)-tetraene]-15’-carboxamide	1558895: Inhibition of recombinant C-terminal His6x-tagged human Mcl-1 (171 to 327 residues) interaction with biotinylated human Bim (51 to 76 residues) incubated for 60 mins in presence of 5 nM biotin-Bim by HTRF assay	ki	0.0001	uM
(3’R,4S,6’R,7’S,8’E,15’R)-7-chloro-7’,15’-dihydroxy-12’-methyl-13’-oxospiro[2,3-dihydro-1H-naphthalene-4,22’-20-oxa-1,12-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16(25),17,19(24)-tetraene]-15’-carboxylic acid	1558895: Inhibition of recombinant C-terminal His6x-tagged human Mcl-1 (171 to 327 residues) interaction with biotinylated human Bim (51 to 76 residues) incubated for 60 mins in presence of 5 nM biotin-Bim by HTRF assay	ki	0.0001	uM
(3’R,4S,6’R,7’S,8’E,15’R)-7-chloro-15’-hydroxy-7’-methoxy-12’-methyl-13’-oxospiro[2,3-dihydro-1H-naphthalene-4,22’-20-oxa-1,12-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16(25),17,19(24)-tetraene]-15’-carboxylic acid	1558895: Inhibition of recombinant C-terminal His6x-tagged human Mcl-1 (171 to 327 residues) interaction with biotinylated human Bim (51 to 76 residues) incubated for 60 mins in presence of 5 nM biotin-Bim by HTRF assay	ki	0.0001	uM
(3’R,4S,6’R,7’S,8’E,15’R)-7-chloro-N-(dimethylsulfamoyl)-15’-hydroxy-12’-methyl-7’-(2-morpholin-4-ylethoxy)-13’-oxospiro[2,3-dihydro-1H-naphthalene-4,22’-20-oxa-1,12-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16(25),17,19(24)-tetraene]-15’-carboxamide	1558895: Inhibition of recombinant C-terminal His6x-tagged human Mcl-1 (171 to 327 residues) interaction with biotinylated human Bim (51 to 76 residues) incubated for 60 mins in presence of 5 nM biotin-Bim by HTRF assay	ki	0.0001	uM
(3’R,4S,6’R,7’S,8’E,16’R)-7-chloro-7’,16’-dihydroxy-13’-methyl-14’-oxospiro[2,3-dihydro-1H-naphthalene-4,23’-21-oxa-1,13-diazatetracyclo[15.7.2.03,6.020,25]hexacosa-8,17(26),18,20(25)-tetraene]-16’-carboxylic acid	1558895: Inhibition of recombinant C-terminal His6x-tagged human Mcl-1 (171 to 327 residues) interaction with biotinylated human Bim (51 to 76 residues) incubated for 60 mins in presence of 5 nM biotin-Bim by HTRF assay	ki	0.0001	uM
(3’R,4S,6’R,7’S,8’E,15’R)-7-chloro-N-(dimethylsulfamoyl)-7’-[2-(3-fluoroazetidin-1-yl)ethoxy]-15’-hydroxy-12’-methyl-13’-oxospiro[2,3-dihydro-1H-naphthalene-4,22’-20-oxa-1,12-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16(25),17,19(24)-tetraene]-15’-carboxamide	1558895: Inhibition of recombinant C-terminal His6x-tagged human Mcl-1 (171 to 327 residues) interaction with biotinylated human Bim (51 to 76 residues) incubated for 60 mins in presence of 5 nM biotin-Bim by HTRF assay	ki	0.0001	uM
(3’R,4S,6’R,7’S,8’E,15’R)-7-chloro-N-(dimethylsulfamoyl)-15’-hydroxy-7’-[2-(3-methoxyazetidin-1-yl)ethoxy]-12’-methyl-13’-oxospiro[2,3-dihydro-1H-naphthalene-4,22’-20-oxa-1,12-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16(25),17,19(24)-tetraene]-15’-carboxamide	1558895: Inhibition of recombinant C-terminal His6x-tagged human Mcl-1 (171 to 327 residues) interaction with biotinylated human Bim (51 to 76 residues) incubated for 60 mins in presence of 5 nM biotin-Bim by HTRF assay	ki	0.0001	uM
(3’R,4S,6’R,7’S,8’E,15’R)-7-chloro-7’-[2-(2,2-difluoroethoxy)ethoxy]-N-(dimethylsulfamoyl)-15’-hydroxy-12’-methyl-13’-oxospiro[2,3-dihydro-1H-naphthalene-4,22’-20-oxa-1,12-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16(25),17,19(24)-tetraene]-15’-carboxamide	1558895: Inhibition of recombinant C-terminal His6x-tagged human Mcl-1 (171 to 327 residues) interaction with biotinylated human Bim (51 to 76 residues) incubated for 60 mins in presence of 5 nM biotin-Bim by HTRF assay	ki	0.0001	uM
(3’R,4S,6’R,7’S,8’E,15’R)-7-chloro-N-(dimethylsulfamoyl)-7’-[2-(1,1-dioxo-1,4-thiazinan-4-yl)ethoxy]-15’-hydroxy-12’-methyl-13’-oxospiro[2,3-dihydro-1H-naphthalene-4,22’-20-oxa-1,12-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16(25),17,19(24)-tetraene]-15’-carboxamide	1558895: Inhibition of recombinant C-terminal His6x-tagged human Mcl-1 (171 to 327 residues) interaction with biotinylated human Bim (51 to 76 residues) incubated for 60 mins in presence of 5 nM biotin-Bim by HTRF assay	ki	0.0001	uM
(3’R,4S,6’R,7’S,8’E,15’R)-7-chloro-15’-hydroxy-7’-methoxy-12’-methyl-N-methylsulfonyl-13’-oxospiro[2,3-dihydro-1H-naphthalene-4,22’-20-oxa-1,12-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16(25),17,19(24)-tetraene]-15’-carboxamide	1558895: Inhibition of recombinant C-terminal His6x-tagged human Mcl-1 (171 to 327 residues) interaction with biotinylated human Bim (51 to 76 residues) incubated for 60 mins in presence of 5 nM biotin-Bim by HTRF assay	ki	0.0001	uM
(3’R,4S,6’R,7’S,8’E,11’S,12’R)-7-chloro-11’,12’-dimethyl-7’-(2-morpholin-4-ylethoxy)-13’,13’-dioxospiro[2,3-dihydro-1H-naphthalene-4,22’-20-oxa-13lambda6-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16(25),17,19(24)-tetraene]-15’-one	1845330: Inhibition of recombinant His6-tagged human MCL1 (171 to 327 residues) expressed in Escherichia coli and biotinylated Bim BH3 peptide interaction using Biotin-DMRPEIWIAQELRRIGDEFNAYYARR as substrate incubated for 60 mins by TR-FRET analysis	ki	0.0001	uM

CTD chemical–gene interactions

323 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Sorafenib	affects cotreatment, decreases expression, affects folding, increases activity, decreases response to substance (+4 more)	19
benzyloxycarbonylleucyl-leucyl-leucine aldehyde	decreases expression, decreases reaction, affects cotreatment, increases expression, affects reaction (+4 more)	17
Arsenic Trioxide	decreases reaction, increases reaction, affects cotreatment, affects binding, increases cleavage (+2 more)	16
Resveratrol	decreases reaction, increases reaction, affects cotreatment, increases expression, increases activity (+3 more)	12
Bortezomib	decreases reaction, increases abundance, increases cleavage, increases reaction, affects cotreatment (+3 more)	11
Quercetin	increases ubiquitination, decreases reaction, increases localization, decreases response to substance, increases reaction (+4 more)	10
Benzo(a)pyrene	increases stability, affects cotreatment, decreases reaction, decreases methylation, increases methylation (+8 more)	9
sodium arsenite	increases abundance, decreases expression, decreases cleavage, increases reaction, decreases ubiquitination (+5 more)	7
alvocidib	increases reaction, decreases response to substance, affects expression, affects cotreatment, decreases expression	7
Cycloheximide	affects cotreatment, increases response to substance, increases reaction, decreases expression, decreases reaction	6
Tretinoin	decreases reaction, increases expression, affects cotreatment, decreases expression	6
Cadmium Chloride	increases abundance, increases expression, decreases reaction, decreases expression, affects cotreatment	6
bisphenol A	affects expression, decreases expression, increases expression, affects cotreatment	5
2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one	increases degradation, decreases reaction, affects expression, affects cotreatment, decreases expression	5
ABT-737	affects reaction, increases abundance, increases reaction, decreases activity, decreases response to substance (+5 more)	5
ON 01910	increases reaction, decreases expression	5
(+)-JQ1 compound	affects cotreatment, affects expression, decreases expression	5
Cisplatin	increases reaction, decreases expression, decreases response to substance, increases degradation, decreases reaction (+2 more)	5
Valproic Acid	affects expression, decreases expression, increases expression	5
4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)imidazole	decreases stability, increases expression, affects cotreatment, decreases expression, decreases reaction	4
2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one	increases expression, decreases expression, decreases reaction, increases phosphorylation	4
venetoclax	affects cotreatment, decreases expression, decreases reaction, increases reaction, affects reaction (+1 more)	4
Celecoxib	decreases expression	4
Wortmannin	increases reaction, affects cotreatment, decreases reaction, increases abundance, decreases cleavage (+4 more)	4
Acetylcysteine	decreases expression, decreases reaction, increases reaction, affects cotreatment	4
Plant Extracts	affects expression, decreases expression, increases cleavage, increases expression	4
cobaltous chloride	decreases expression, increases degradation, increases cleavage, increases expression, decreases reaction	3
PI103	increases expression, affects cotreatment, decreases response to substance, decreases expression, decreases reaction	3
NVP-BKM120	decreases expression, decreases reaction, affects reaction, increases reaction, affects cotreatment	3
Arsenic	decreases reaction, increases abundance, decreases expression, decreases cleavage, decreases ubiquitination (+5 more)	3

ChEMBL screening assays

560 unique, capped per target: 554 binding, 6 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3383446	Binding	Inhibition of Mcl1/Bid (unknown origin) interaction	Pro-apoptotic meiogynin A derivatives that target Bcl-xL and Mcl-1. — *Bioorg Med Chem Lett*
CHEMBL1614529	Functional	PUBCHEM_BIOASSAY: Dose Response Confirmation for Mcl-1/Noxa Interaction Inhibitors. (Class of assay: confirmatory) [Related pubchem assays: 1022 (Primary screen preceding this dose-response assay.)]	PubChem BioAssay data set

Cellosaurus cell lines

6 cell lines: 4 cancer cell line, 2 transformed cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_B3AW	Abcam HEK293T MCL1 KO	Transformed cell line	Female
CVCL_D7UV	Ubigene A-549 MCL1 KO	Cancer cell line	Male
CVCL_D8QE	Ubigene HCT 116 MCL1 KO	Cancer cell line	Male
CVCL_D9JZ	Ubigene HEK293 MCL1 KO	Transformed cell line	Female
CVCL_E0HP	Ubigene HeLa MCL1 KO	Cancer cell line	Female
CVCL_KW15	InCELL Hunter U2OS MCL1-BIM Protein Binding	Cancer cell line	Female

Clinical trials (associated diseases)

Via MONDO — disease-level, not drug-specific.

Predicted chemistry — Sugi Predict

The predicted patent-compound landscape for MCL1 across ~30M SureChEMBL compounds — explore on Sugi Predict.