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
• Druggable target: yes — 19 molecules with ChEMBL bioactivity
• Cancer dependency (DepMap): dependent in 63.7% of screened cell lines
• MANE Select transcript: NM_021960

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: 8 — 5 protein_coding, 2 retained_intron, 1 protein_coding_CDS_not_defined

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

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.

FANTOM5 promoters (2 alternative TSS)

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

Top tissues by expression

304 total, 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

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

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)

154 targeting MCL1, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

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

DepMap (CRISPR cell-line fitness): dependent in 63.7% of screened cell lines.

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

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	mcl1b	ENSDARG00000008363
danio_rerio	mcl1a	ENSDARG00000009779
mus_musculus	Mcl1	ENSMUSG00000038612
rattus_norvegicus	Mcl1	ENSRNOG00000063678
caenorhabditis_elegans		WBGENE00000423

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

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): Q07820, A0A087WT64, A0A7I2V2W2

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 (52 total): mutagenesis site 14, helix 11, 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, strand 1

Structure

Experimental structures (PDB)

144 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
8VJP	X-RAY DIFFRACTION	1.13
9PQ7	X-RAY DIFFRACTION	1.24
9PQ5	X-RAY DIFFRACTION	1.28
6UDV	X-RAY DIFFRACTION	1.35
9UGP	X-RAY DIFFRACTION	1.39
8G3S	X-RAY DIFFRACTION	1.4
5W89	X-RAY DIFFRACTION	1.42
5C3F	X-RAY DIFFRACTION	1.43
8G3X	X-RAY DIFFRACTION	1.46
8H7B	X-RAY DIFFRACTION	1.46
8SVY	X-RAY DIFFRACTION	1.47
6OQD	X-RAY DIFFRACTION	1.48
5FC4	X-RAY DIFFRACTION	1.5
6UDT	X-RAY DIFFRACTION	1.5
4HW4	X-RAY DIFFRACTION	1.53
9PQ6	X-RAY DIFFRACTION	1.53
2NL9	X-RAY DIFFRACTION	1.55
4WMU	X-RAY DIFFRACTION	1.55
8EKX	X-RAY DIFFRACTION	1.55
6UA3	X-RAY DIFFRACTION	1.55
8T6F	X-RAY DIFFRACTION	1.56
4BPJ	X-RAY DIFFRACTION	1.6
6FS1	X-RAY DIFFRACTION	1.6
6O6F	X-RAY DIFFRACTION	1.6
6OQB	X-RAY DIFFRACTION	1.6
6QFQ	X-RAY DIFFRACTION	1.6
9Z3V	X-RAY DIFFRACTION	1.6
6P3P	X-RAY DIFFRACTION	1.61
3KJ0	X-RAY DIFFRACTION	1.7
4WMR	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 — 5MES, 5MEV, 6QB3, 6QB4, 6QB6, 6QFC, 8AV9

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): 127–128 (cleavage; by caspase-3); 157–158 (cleavage; by caspase-3)

Post-translational modifications (9): 121, 159, 162, 163, 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
136	reduced ubiquitination.
157	abolishes formation of 23 and 21 kda cleavage products by casp3. abolishes cleavage by caspase-3; when associated with a
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

8 pathways

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

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

Rollup of top-6 pathways:

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

Rollup of top GO terms by namespace:

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

Protein interactions and networks

STRING

3880 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MCL1	PMAIP1	Q13794	999
MCL1	BCL2L11	O43521	999
MCL1	BECN1	Q14457	994
MCL1	ATG12	O94817	985
MCL1	HRK	O00198	982
MCL1	BOK	Q9UMX3	982
MCL1	BCL2L2-PABPN1	Q92843	975
MCL1	BMF	Q96LC9	961
MCL1	VDAC1	P21796	961
MCL1	BBC3	Q96PG8	949
MCL1	RTL10	Q7L3V2	942
MCL1	BIK	Q13323	920
MCL1	BAX	P55269	915
MCL1	TP53	P04637	884
MCL1	BAK1	Q16611	871

IntAct

170 interactions, top by confidence:

A	B	Type	Score
BAK1	MCL1	psi-mi:“MI:0915”(physical association)	0.960
MCL1	BAK1	psi-mi:“MI:0915”(physical association)	0.960
MCL1	BAK1	psi-mi:“MI:0914”(association)	0.960
BCL2L11	MCL1	psi-mi:“MI:0407”(direct interaction)	0.950
MCL1	BCL2L11	psi-mi:“MI:0915”(physical association)	0.950
BCL2L11	MCL1	psi-mi:“MI:0915”(physical association)	0.950
MCL1	BCL2L11	psi-mi:“MI:0914”(association)	0.950
BCL2L11	BAX	psi-mi:“MI:0915”(physical association)	0.940
BAX	BCL2L11	psi-mi:“MI:0914”(association)	0.940
BCL2L11	BCL2	psi-mi:“MI:0914”(association)	0.930
BCL2L11	BCL2L1	psi-mi:“MI:0915”(physical association)	0.930
BAX	MCL1	psi-mi:“MI:0915”(physical association)	0.910

BioGRID (392): BCL2L11 (Protein-peptide), BMF (Protein-peptide), BBC3 (Protein-peptide), PMAIP1 (Protein-peptide), MCL1 (Affinity Capture-Western), BID (Affinity Capture-Western), HUWE1 (Affinity Capture-Western), TRAF6 (Affinity Capture-Western), TRAF6 (Reconstituted Complex), MCL1 (Biochemical Activity), MCL1 (Affinity Capture-RNA), MCL1 (Two-hybrid), BID (Protein-peptide), BCL2L11 (Protein-peptide), BIK (Protein-peptide)

ESM2 similar proteins: A0A1D6HQ92, A2WSZ6, A2XX39, A2ZVY5, A6NIH7, B4FR29, B9Q0C2, F4IVL6, O60291, P04294, P04413, P49727, P68350, Q05A36, Q07820, Q0J7T6, Q0JAI1, Q2QNS6, Q2QPW2, Q3UE17, Q42840, Q53JI9, Q53K52, Q58CZ0, Q5R4R7, Q5VM82, Q5VRL3, Q6IMP4, Q6L5G1, Q6UDF4, Q6UDI9, Q6UDL6, Q6ZBS8, Q750B5, Q75CM4, Q7XDY9, Q7XLY8, Q7YRZ9, Q80TL4, Q84MH1

Diamond homologs: O02703, O02718, O77737, P10415, P10417, P49950, P53563, P70345, Q00709, Q07812, Q07813, Q07816, Q07817, Q07820, Q1RMX3, Q45T69, Q63690, Q64373, Q6R755, Q7YRZ9, Q90343, Q91827, Q92843, Q9JJV8, P97287, Q8HYS5, Q9J5G4, Q9Z1P3, Q90ZN1, Q99M66, Q9HD36, Q6VZT9, Q07440

SIGNOR signaling

28 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”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 89 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
Signaling by FLT3 ITD and TKD mutants	5	62.4×	1e-06
Activation of BH3-only proteins	7	57.0×	3e-09
Intrinsic Pathway for Apoptosis	10	48.0×	2e-12
TP53 Regulates Transcription of Genes Involved in Cytochrome C Release	5	44.6×	6e-06
FLT3 Signaling	6	34.0×	2e-06
Apoptosis	10	27.5×	4e-10
FOXO-mediated transcription	5	27.5×	4e-05
Programmed Cell Death	10	24.0×	1e-09

GO biological processes:

GO term	Partners	Fold	FDR
positive regulation of release of cytochrome c from mitochondria	10	98.2×	2e-15
release of cytochrome c from mitochondria	8	72.0×	6e-11
apoptotic mitochondrial changes	6	68.2×	5e-08
positive regulation of intrinsic apoptotic signaling pathway	8	49.4×	1e-09
regulation of mitochondrial membrane potential	5	34.9×	3e-05
positive regulation of protein-containing complex assembly	8	34.6×	2e-08
intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress	5	30.9×	6e-05
extrinsic apoptotic signaling pathway in absence of ligand	5	30.0×	6e-05

Disease & clinical

Cancer significance

Clinical variants and AI predictions

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

Top pathogenic / likely-pathogenic (0)

SpliceAI

427 predictions. Top by Δscore:

Variant	Effect	Δscore
1:150577487:CCATC:C	acceptor_gain	1.0000
1:150577488:CATC:C	acceptor_gain	1.0000
1:150577488:CATCC:C	acceptor_gain	1.0000
1:150578243:CCCAG:C	donor_gain	1.0000
1:150578305:T:A	donor_gain	1.0000
1:150578490:GCCT:G	acceptor_loss	1.0000
1:150578491:CCTGA:C	acceptor_loss	1.0000
1:150578492:C:CC	acceptor_gain	1.0000
1:150578838:CTTA:C	donor_loss	1.0000
1:150578839:TTA:T	donor_loss	1.0000
1:150578840:TA:T	donor_loss	1.0000
1:150578841:A:AC	donor_gain	1.0000
1:150578841:A:AG	donor_loss	1.0000
1:150578842:C:CC	donor_gain	1.0000
1:150578842:C:CT	donor_loss	1.0000
1:150577490:TC:T	acceptor_gain	0.9900
1:150577491:CC:C	acceptor_gain	0.9900
1:150577491:CCTAG:C	acceptor_loss	0.9900
1:150577492:C:G	acceptor_loss	0.9900
1:150577493:T:A	acceptor_loss	0.9900
1:150578237:AACTT:A	donor_loss	0.9900
1:150578238:ACTTA:A	donor_loss	0.9900
1:150578239:CTT:C	donor_loss	0.9900
1:150578240:TTA:T	donor_loss	0.9900
1:150578241:TAC:T	donor_loss	0.9900
1:150578242:A:AT	donor_loss	0.9900
1:150578242:AC:A	donor_gain	0.9900
1:150578243:C:CT	donor_loss	0.9900
1:150578243:CC:C	donor_gain	0.9900
1:150578284:A:AC	donor_gain	0.9900

AlphaMissense

2236 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:150577397:C:T	G344D	1.000
1:150577400:G:T	A343D	1.000
1:150577403:C:T	G342E	1.000
1:150577404:C:G	G342R	1.000
1:150577404:C:T	G342R	1.000
1:150577409:C:T	G340E	1.000
1:150577410:C:G	G340R	1.000
1:150577410:C:T	G340R	1.000
1:150577412:G:T	A339D	1.000
1:150577418:C:T	G337D	1.000
1:150577421:G:T	A336E	1.000
1:150577471:G:C	F319L	1.000
1:150577471:G:T	F319L	1.000
1:150577473:A:G	F319L	1.000
1:150577474:G:C	F318L	1.000
1:150577474:G:T	F318L	1.000
1:150577476:A:G	F318L	1.000
1:150578244:C:A	W312C	1.000
1:150578244:C:G	W312C	1.000
1:150578246:A:G	W312R	1.000
1:150578246:A:T	W312R	1.000
1:150578265:C:A	W305C	1.000
1:150578265:C:G	W305C	1.000
1:150578267:A:G	W305R	1.000
1:150578267:A:T	W305R	1.000
1:150578368:C:T	G271D	1.000
1:150578391:C:A	R263S	1.000
1:150578391:C:G	R263S	1.000
1:150578392:C:A	R263M	1.000
1:150578392:C:G	R263T	1.000

dbSNP variants (sampled 300 via entrez): RS1000303125 (1:150578578 G>A), RS1000824081 (1:150574082 C>A), RS1001151771 (1:150574253 CAAAA>C,CAAA,CAAAAA), RS1001346754 (1:150576142 TATATGCACACAGCTA>T), RS1001856748 (1:150578164 T>C), RS1001994935 (1:150576819 G>A), RS1002896056 (1:150577003 T>G), RS1003275247 (1:150576736 A>G), RS1003639390 (1:150580788 A>G), RS1003670330 (1:150580961 C>A,T), RS1004335558 (1:150579397 C>A,G,T), RS1004824890 (1:150579674 CTT>C,CT,CTTT), RS1005065749 (1:150579552 G>A,C,T), RS1005269262 (1:150578141 C>G,T), RS1006270309 (1:150576705 G>A,C)

Disease associations

OMIM: gene MIM:159552 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

20 associations (top):

Study	Trait	p-value
GCST001266_1	Melanoma	9.000000e-11
GCST001966_1	Rhegmatogenous retinal detachment	1.000000e-07
GCST004606_172	Eosinophil count	2.000000e-10
GCST004624_198	Sum eosinophil basophil counts	4.000000e-11
GCST005196_187	Coronary artery disease	3.000000e-07
GCST005977_25	Monocyte count	1.000000e-10
GCST006585_2674	Blood protein levels	2.000000e-07
GCST007429_96	Lung function (FVC)	2.000000e-31
GCST007432_105	FEV1	2.000000e-21
GCST008480_2	Lung function (FEV1)	4.000000e-09
GCST008482_2	Lung function (FVC)	6.000000e-09
GCST009597_80	Multiple sclerosis	1.000000e-06
GCST009801_1	Coffee consumption	1.000000e-10
GCST010002_366	Refractive error	3.000000e-15
GCST011946_3	White matter hyperintensity volume	7.000000e-07
GCST011947_54	White matter hyperintensity volume	1.000000e-07
GCST011949_21	White matter hyperintensity volume (adjusted for hypertension)	4.000000e-06
GCST011950_16	White matter hyperintensity volume (adjusted for hypertension)	1.000000e-06
GCST011953_16	White matter hyperintensity volume x hypertension interaction (2df)	6.000000e-06
GCST90002390_16	Mean corpuscular hemoglobin	8.000000e-10

EFO canonical traits (8, from GWAS)

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)

Molecules with ChEMBL bioactivity

19 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 401,431 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL3137309	VENETOCLAX	4	9,389
CHEMBL1200938	METHYSERGIDE MALEATE	4	4
CHEMBL1201119	LIOTHYRONINE SODIUM	4	3,058
CHEMBL1503	OMEPRAZOLE	4	52,284
CHEMBL290106	BITHIONOL	4	6,439
CHEMBL3187985	APOMORPHINE HYDROCHLORIDE	4	5,278
CHEMBL496	HEXACHLOROPHENE	4	26,164
CHEMBL6466	COUMARIN	4	202,873
CHEMBL728	PROCHLORPERAZINE	4	25,844
CHEMBL297453	EPIGALOCATECHIN GALLATE	3	22,804
CHEMBL51483	GOSSYPOL	3	13,973
CHEMBL408194	OBATOCLAX	3	2,914
CHEMBL443684	NAVITOCLAX	3	4,791
CHEMBL12208	HYMECROMONE	2	18,363
CHEMBL376408	ABT 737	1	4,288
CHEMBL4297482	AZD-5991	1	947
CHEMBL4446378	TAPOTOCLAX	1	1,476
CHEMBL4650225	MURIZATOCLAX	1	534
CHEMBL6033457	ABBV-467	1	8

PharmGKB: 1 entry (VIP=true, CPIC=false)

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)

1451 measured of 1557 human assays (1674 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
2-[(2,5-dimethoxybenzylidene)amino]-4,5-bis(2-furyl)-3-furonitrile	EC50	0.00197 nM
CHEMBL5394656	KI	0.032 nM
CHEMBL5405517	KI	0.041 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]-1,4,6,7-tetrahydropyrano[4,3-b]pyrrole-2-carboxamide	IC50	0.135 nM	US-10703733: MCL-1 inhibitors
(3’R,4S,6’R,7’S,8’E,11’S,12’R)-7-chloro-7’-methoxy-11’,12’-dimethyl-13’,13’-dioxo-7’-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-ylmethyl)spiro[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	0.263 nM	US-10821115: Compounds that inhibit Mcl-1 protein
(3’R,4S,6’R,7’R,8’E,11’S,12’R)-7-chloro-7’-hydroxy-11’,12’-dimethyl-13’,13’-dioxo-7’-(2H-triazol-4-yl)spiro[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	0.333 nM	US-10821115: Compounds that inhibit Mcl-1 protein
7-(3-((4-Borono-3-formylphenoxy)methyl)-1,5-dimethyl-1Hpyrazol-4-yl)-3-(3-(naphthalen-1-yloxy)propyl)-1H-indole-2-carboxylic acid, 5	KI	0.9 nM
7-(3-((3-Acetyl-4-boronophenoxy)methyl)-1,5-dimethyl-1H-pyrazol-4-yl)-3-(3-(naphthalen-1-yloxy)propyl)-1H-indole-2-carboxylic acid, 6	KI	1.2 nM
7-(3-((4-Borono-3-formylphenoxy)methyl)-1,5-dimethyl-1Hpyrazol-4-yl)-1-methyl-3-(3-(naphthalen-1-yloxy)propyl)-1H-indole-2-carboxylic acid, 11	KI	1.2 nM
Mcl-1 inhibitor 12	KI	1.6 nM
(S)-N-((4-(((1,4-dioxan-2-yl)methyl)amino)-3- nitrophenyl)sulfonyl)-2-((1H-pyrrolo[2,3-b]pyridin- 5-yl)oxy)-4-(4-((6-(4-chlorophenyl)spiro[3.5]non-6- en-7-yl)methyl)piperazin-1-yl)benzamide	IC50	2 nM	US-10221174: N-(phenylsulfonyl)benzamides and related compounds as BCL-2 inhibitors
(R)-N-((4-(((1,4-dioxan-2-yl)methyl)amino)-3- nitrophenyl)sulfonyl)-2-((1H-pyrrolo[2,3-b]pyridin- 5-yl)oxy)-4-(4-((6-(4-chlorophenyl)-2- oxaspiro[3.5]non-6-en-7-yl)methyl)piperazin-1- yl)benzamide	IC50	2.4 nM	US-10221174: N-(phenylsulfonyl)benzamides and related compounds as BCL-2 inhibitors
ABT-199	IC50	4.4 nM
(5Z)-2-azanylidene-5-[[5-(3-chlorophenyl)furan-2-yl]methylidene]-3-(1,3-thiazol-2-yl)-1,3-thiazolidin-4-one	EC50	10 nM
4-(4-{[2-(4-chlorophenyl)phenyl]methyl}piperazin-1-yl)-N-[(4-{[(2R)-4-(dimethylamino)-1-(phenylsulfanyl)butan-2-yl]amino}-3-nitrobenzene)sulfonyl]benzamide	IC50	14 nM
7-(3-((3-formylphenoxy)methyl)-1,5-dimethyl-1H-pyrazol-4-yl)-3-(3-(naphthalen-1-yloxy)propyl)-1H-indole-2-carboxylic acid, 7	KI	16 nM
2-(2-furanyl)-4-quinolinecarboxylic acid [2-[4-[2-furanyl(oxo)methyl]-1-piperazinyl]-2-oxoethyl] ester	EC50	16.3 nM
MLS000523248	IC50	19.8 nM
4-[[2-[(4-keto-6-methyl-1H-pyrimidin-2-yl)thio]acetyl]amino]benzoic acid ethyl ester	IC50	23 nM
(E)-3-amino-2-[1-oxo-2-[[5-(propan-2-ylamino)-1,3,4-thiadiazol-2-yl]thio]ethyl]-2-butenenitrile	IC50	23 nM
4-methoxy-N-(6-methoxy-4H-indeno[1,2-d][1,3]thiazol-2-yl)benzamide	IC50	23 nM
130E7	IC50	27 nM
6-(morpholine-4-carbonyl)-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinoline-4-carboxylic acid	IC50	40.7 nM
7-(3-((4-Boronophenoxy)methyl)-1,5-dimethyl-1H-pyrazol-4-yl)-3-(3-(naphthalen-1-yloxy)propyl)-1H-indole-2-carboxylic acid, 9	KI	44 nM
MLS000530403	IC50	58.8 nM
5-[(4-chlorophenyl)carbamoylamino]-3-methyl-thiophene-2-carboxylic acid ethyl ester	IC50	63.1 nM
7-(3-((3-Acetylphenoxy)methyl)-1,5-dimethyl-1H-pyrazol-4-yl)-3-(3-(naphthalen-1-yloxy)propyl)-1H-indole-2-carboxylic acid, 8	KI	64 nM
Compound I	IC50	67 nM	US-10196404: MCL-1 inhibitors and methods of use thereof
HEXACHLOROPHENE	IC50	98.3 nM
Mcl-1 inhibitor 10	KI	104 nM
3-[(E)-5’-(2-Cyano-ethylsulfanyl)-5,4’-dimethyl-[2,2’]bi[[1,3]dithiolylidene]-4-ylsulfanyl]-propionitrile	IC50	129 nM
Apogossypol derivative, 8n	IC50	150 nM
2,5-bis(chloranyl)-3-(4-methylpiperazin-1-yl)-6-(2-piperidin-1-yl-1,3-thiazol-5-yl)cyclohexa-2,5-diene-1,4-dione	EC50	160 nM
(3aS,4R,9bR)-6,8-dimethyl-4-[4-(morpholin-4-ylsulfonyl)phenyl]-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinoline	EC50	165 nM
2-chloranyl-3-[[4-(diethylamino)phenyl]amino]naphthalene-1,4-dione	EC50	170 nM
130D11	IC50	199 nM
3-[3-(4-chloro-3,5-dimethylphenoxy)propyl]-N-[2-[[2-(1H-indol-3-yl)acetyl]amino]ethylsulfonyl]-1H-indole-2-carboxamide	IC50	200 nM	US-10093646: 1-pyridazin-/triazin-3-yl-piper(-azine)/idine/pyrolidine derivatives and compositions thereof for inhibiting the activity of SHP2
N-((2-(2-((1s,3s)-adamantan-1-yl)acetamido)ethyl)sulfonyl)-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1H-indole-2-carboxamide	IC50	200 nM	US-10093646: 1-pyridazin-/triazin-3-yl-piper(-azine)/idine/pyrolidine derivatives and compositions thereof for inhibiting the activity of SHP2
3-[3-(4-chloro-3,5-dimethylphenoxy)propyl]-N-[2-(pyridine-2-carbonylamino)ethylsulfonyl]-1H-indole-2-carboxamide	IC50	200 nM	US-10093646: 1-pyridazin-/triazin-3-yl-piper(-azine)/idine/pyrolidine derivatives and compositions thereof for inhibiting the activity of SHP2
3-[3-(4-chloro-3,5-dimethylphenoxy)propyl]-N-[2-[(1-cyclopropyl-2,5-dimethylpyrrole-3-carbonyl)amino]ethylsulfonyl]-1H-indole-2-carboxamide	IC50	200 nM	US-10093646: 1-pyridazin-/triazin-3-yl-piper(-azine)/idine/pyrolidine derivatives and compositions thereof for inhibiting the activity of SHP2
N-[2-[(1-benzyl-2,5-dimethylpyrrole-3-carbonyl)amino]ethylsulfonyl]-3-[3-(4-chloro-3,5-dimethylphenoxy)propyl]-1H-indole-2-carboxamide	IC50	200 nM	US-10093646: 1-pyridazin-/triazin-3-yl-piper(-azine)/idine/pyrolidine derivatives and compositions thereof for inhibiting the activity of SHP2
3-[3-(4-chloro-3,5-dimethylphenoxy)propyl]-N-[2-[[2,5-dimethyl-1-(pyridin-4-ylmethyl)pyrrole-3-carbonyl]amino]ethylsulfonyl]-1H-indole-2-carboxamide	IC50	200 nM	US-10093646: 1-pyridazin-/triazin-3-yl-piper(-azine)/idine/pyrolidine derivatives and compositions thereof for inhibiting the activity of SHP2
N-[2-[(1-benzylindole-3-carbonyl)amino]ethylsulfonyl]-3-[3-(4-chloro-3,5-dimethylphenoxy)propyl]-1H-indole-2-carboxamide	IC50	200 nM	US-10093646: 1-pyridazin-/triazin-3-yl-piper(-azine)/idine/pyrolidine derivatives and compositions thereof for inhibiting the activity of SHP2
3-[3-(4-chloro-3,5-dimethylphenoxy)propyl]-N-[3-(oxan-4-ylcarbamoyl)phenyl]sulfonyl-1H-indole-2-carboxamide	IC50	200 nM	US-10093646: 1-pyridazin-/triazin-3-yl-piper(-azine)/idine/pyrolidine derivatives and compositions thereof for inhibiting the activity of SHP2
6-chloro-3-[3-(4-chloro-3,5-dimethylphenoxy)propyl]-N-(3-methylphenyl)sulfonyl-1H-indole-2-carboxamide	IC50	200 nM	US-10093646: 1-pyridazin-/triazin-3-yl-piper(-azine)/idine/pyrolidine derivatives and compositions thereof for inhibiting the activity of SHP2
N-(3-bromophenyl)sulfonyl-6-chloro-3-[3-(4-chloro-3,5-dimethylphenoxy)propyl]-1H-indole-2-carboxamide	IC50	200 nM	US-10093646: 1-pyridazin-/triazin-3-yl-piper(-azine)/idine/pyrolidine derivatives and compositions thereof for inhibiting the activity of SHP2
6-chloro-3-[3-(4-chloro-3,5-dimethylphenoxy)propyl]-N-[3-(4-methoxyphenoxy)phenyl]sulfonyl-1H-indole-2-carboxamide	IC50	200 nM	US-10093646: 1-pyridazin-/triazin-3-yl-piper(-azine)/idine/pyrolidine derivatives and compositions thereof for inhibiting the activity of SHP2
6-chloro-3-[3-(4-chloro-3,5-dimethylphenoxy)propyl]-N-(4-phenoxyphenyl)sulfonyl-1H-indole-2-carboxamide	IC50	200 nM	US-10093646: 1-pyridazin-/triazin-3-yl-piper(-azine)/idine/pyrolidine derivatives and compositions thereof for inhibiting the activity of SHP2
6-chloro-3-[3-(4-chloro-3,5-dimethylphenoxy)propyl]-N-[2-[(2-methylfuran-3-carbonyl)amino]ethylsulfonyl]-1H-indole-2-carboxamide	IC50	200 nM	US-10093646: 1-pyridazin-/triazin-3-yl-piper(-azine)/idine/pyrolidine derivatives and compositions thereof for inhibiting the activity of SHP2
6-chloro-3-[3-(4-chloro-3,5-dimethylphenoxy)propyl]-N-[2-[(3-phenoxybenzoyl)amino]ethylsulfonyl]-1H-indole-2-carboxamide	IC50	200 nM	US-10093646: 1-pyridazin-/triazin-3-yl-piper(-azine)/idine/pyrolidine derivatives and compositions thereof for inhibiting the activity of SHP2

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

1939 with measured affinity, of 3146 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
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
(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
17-chloro-5,14,22-trimethyl-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’S,4S,7’S,8’Z,11’S,12’R)-7’-[[(9aS)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]methyl]-7-chloro-8’-fluoro-11’,12’-dimethyl-13’,13’-dioxospiro[2,3-dihydro-1H-naphthalene-4,22’-20-oxa-13lambda6-thia-1,6,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16(25),17,19(24)-tetraene]-15’-one	1694521: Inhibition of Terbium-labeled BIM BH3 peptide binding to MCL1 (unknown origin) incubated for 60 mins by HTRF assay	ki	0.0001	uM

CTD chemical–gene interactions

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

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

0 trials via MONDO — disease-level, not drug-specific.