CBLC

Summary

CBLC (Cbl proto-oncogene C, HGNC:15961) is a protein-coding gene on chromosome 19q13.32, encoding E3 ubiquitin-protein ligase CBL-C (Q9ULV8). Acts as an E3 ubiquitin-protein ligase, which accepts ubiquitin from specific E2 ubiquitin-conjugating enzymes, and then transfers it to substrates promoting their degradation by the proteasome. In precision oncology, CBLC EXPRESSION is associated with resistance to Olaparib in Breast Carcinoma (CIViC Level D).

This gene encodes a member of the Cbl family of E3 ubiquitin ligases. Cbl proteins play important roles in cell signaling through the ubiquitination and subsequent downregulation of tyrosine kinases. Expression of this gene may be restricted to epithelial cells, and alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene.

Source: NCBI Gene 23624 — RefSeq curated summary.

At a glance

• GWAS associations: 15
• Clinical variants (ClinVar): 94 total
• Regional missense constraint (gnomAD): 1 of 3 regions constrained (≈3% of expected missense variation)
• GTEx eGene: eQTL in 8 tissues, sQTL in 4 (q < 0.05)
• Precision-oncology evidence (CIViC): 1 curated variant–drug association
• Constraint (gnomAD): pLI 0.00 (LoF-tolerant), LOEUF 1.06 (unconstrained)
• MANE Select transcript: NM_012116

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:15961
Approved symbol	CBLC
Name	Cbl proto-oncogene C
Location	19q13.32
Locus type	gene with protein product
Status	Approved
Aliases	CBL-3, CBL-SL, RNF57
Ensembl gene	ENSG00000142273
Ensembl biotype	protein_coding
OMIM	608453
Entrez	23624

Gene structure

Transcript identifiers

Ensembl transcripts: 23 — 15 protein_coding, 8 nonsense_mediated_decay

MANE Select: ENST00000647358

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 1

ENST00000647358, ENST00000341505, ENST00000647063, ENST00000880087, ENST00000880088, ENST00000880089, ENST00000880090, ENST00000880091, ENST00000880092, ENST00000880093, ENST00000880094, ENST00000880095, ENST00000880096, ENST00000880097, ENST00000916799, ENST00000997577, ENST00000997578, ENST00000997580, ENST00001054999, ENST00001055000, ENST00001073502, ENST00001073503, ENST00001143484

RefSeq mRNA: 2 — MANE Select: NM_012116 NM_001130852, NM_012116

CCDS: CCDS12643, CCDS46109

Canonical transcript exons

ENST00000647358 — 11 exons

Exon	Start	End
ENSE00000953175	44780905	44781051
ENSE00000953176	44781207	44781363
ENSE00000953177	44782370	44782491
ENSE00000953178	44784264	44784401
ENSE00000953179	44790004	44790091
ENSE00000953180	44792383	44792514
ENSE00000953181	44793474	44793620
ENSE00000953182	44794204	44794281
ENSE00000953183	44800381	44800450
ENSE00003821766	44777890	44778284
ENSE00003833186	44800551	44800652

Expression profiles

Bgee: expression breadth ubiquitous, 135 present calls, max score 95.31.

FANTOM5 (CAGE): breadth broad, TPM avg 5.3077 / max 195.6755, expressed in 365 samples.

Highest expression (Bgee): mucosa of transverse colon, lower esophagus mucosa, skin of abdomen, skin of leg, esophagus mucosa.

Genetic regulation across tissues (GTEx eQTL / sQTL)

CBLC is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 8 tissues and its splicing (sQTL) in 4 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

12 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Skin Sun Exposed Lower leg	sqtl	9.4e-13	-0.87	19:44794222:C:T
Thyroid	eqtl	4.1e-11	-0.65	19:44780626:C:A
Skin Not Sun Exposed Suprapubic	sqtl	6.2e-08	-1.90	19:44784417:G:C
Esophagus Mucosa	sqtl	2.3e-07	+0.91	19:44794116:T:A
Skin Sun Exposed Lower leg	eqtl	6.5e-06	+0.32	19:44784417:G:C
Minor Salivary Gland	eqtl	3.3e-05	-0.38	19:44776083:A:G
Skin Not Sun Exposed Suprapubic	eqtl	2.9e-04	+0.42	19:44784417:G:C
Esophagus Mucosa	eqtl	7.3e-03	+0.48	19:44890216:C:T
Stomach	eqtl	9.1e-03	+0.25	19:45453181:G:A
Breast Mammary Tissue	sqtl	2.7e-02	+0.84	19:44002767:A:T
Brain Cortex	eqtl	3.1e-02	-0.97	19:44031646:CT:C
Testis	eqtl	4.9e-02	+0.72	19:45019803:G:C

FANTOM5 promoters

3 alternative TSS:

Promoter ID	TPM avg	Samples expressed
176296	4.9258	358
176298	0.2779	133
176297	0.1040	68

Top tissues by expression

showing 100 of 271 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
mucosa of transverse colon	UBERON:0004991	95.31	gold quality
lower esophagus mucosa	UBERON:0035834	94.11	gold quality
skin of abdomen	UBERON:0001416	91.01	gold quality
skin of leg	UBERON:0001511	90.41	gold quality
esophagus mucosa	UBERON:0002469	90.09	gold quality
duodenum	UBERON:0002114	89.44	gold quality
zone of skin	UBERON:0000014	86.64	gold quality
right lobe of liver	UBERON:0001114	85.62	gold quality
body of pancreas	UBERON:0001150	84.77	gold quality
jejunal mucosa	UBERON:0000399	84.49	gold quality
rectum	UBERON:0001052	82.81	gold quality
small intestine Peyer’s patch	UBERON:0003454	82.74	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	82.66	gold quality
transverse colon	UBERON:0001157	82.40	gold quality
small intestine	UBERON:0002108	81.97	gold quality
minor salivary gland	UBERON:0001830	81.69	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	79.55	gold quality
mouth mucosa	UBERON:0003729	79.16	gold quality
pancreas	UBERON:0001264	78.31	gold quality
saliva-secreting gland	UBERON:0001044	78.09	gold quality
colonic epithelium	UBERON:0000397	77.71	gold quality
ileal mucosa	UBERON:0000331	76.80	silver quality
vagina	UBERON:0000996	76.23	gold quality
body of stomach	UBERON:0001161	76.18	gold quality
gall bladder	UBERON:0002110	76.11	gold quality
metanephros cortex	UBERON:0010533	75.56	gold quality
colonic mucosa	UBERON:0000317	74.34	gold quality
liver	UBERON:0002107	73.63	gold quality
right uterine tube	UBERON:0001302	73.61	gold quality
prostate gland	UBERON:0002367	73.54	gold quality
stomach	UBERON:0000945	72.97	gold quality
intestine	UBERON:0000160	71.76	gold quality
mucosa of sigmoid colon	UBERON:0004993	71.55	gold quality
islet of Langerhans	UBERON:0000006	70.98	gold quality
oral cavity	UBERON:0000167	69.81	silver quality
tonsil	UBERON:0002372	69.23	gold quality
nasal cavity mucosa	UBERON:0001826	69.10	gold quality
large intestine	UBERON:0000059	68.59	gold quality
colon	UBERON:0001155	68.48	gold quality
upper leg skin	UBERON:0004262	67.72	silver quality
adult mammalian kidney	UBERON:0000082	67.60	gold quality
urinary bladder	UBERON:0001255	67.52	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	67.42	gold quality
esophagus	UBERON:0001043	64.74	gold quality
jejunum	UBERON:0002115	64.74	gold quality
vermiform appendix	UBERON:0001154	64.53	gold quality
esophagus squamous epithelium	UBERON:0006920	64.53	silver quality
right lobe of thyroid gland	UBERON:0001119	64.52	gold quality
left lobe of thyroid gland	UBERON:0001120	64.51	gold quality
mucosa of stomach	UBERON:0001199	64.37	gold quality
buccal mucosa cell	CL:0002336	63.90	gold quality
thyroid gland	UBERON:0002046	63.08	gold quality
palpebral conjunctiva	UBERON:0001812	62.26	silver quality
caecum	UBERON:0001153	62.22	gold quality
parotid gland	UBERON:0001831	62.08	gold quality
gingiva	UBERON:0001828	61.91	silver quality
gingival epithelium	UBERON:0001949	61.38	silver quality
penis	UBERON:0000989	61.14	silver quality
fundus of stomach	UBERON:0001160	59.47	gold quality
upper lobe of left lung	UBERON:0008952	59.36	gold quality
nasal cavity epithelium	UBERON:0005384	59.32	gold quality
decidua	UBERON:0002450	59.06	gold quality
left uterine tube	UBERON:0001303	59.04	gold quality
kidney	UBERON:0002113	58.74	gold quality
tongue squamous epithelium	UBERON:0006919	58.43	gold quality
cortex of kidney	UBERON:0001225	58.29	gold quality
gluteal muscle	UBERON:0002000	58.25	gold quality
fallopian tube	UBERON:0003889	58.07	gold quality
triceps brachii	UBERON:0001509	58.05	gold quality
metanephros	UBERON:0000081	57.69	gold quality
upper lobe of lung	UBERON:0008948	57.67	gold quality
mammalian vulva	UBERON:0000997	57.19	silver quality
uterine cervix	UBERON:0000002	57.16	gold quality
pharyngeal mucosa	UBERON:0000355	56.99	gold quality
endocervix	UBERON:0000458	56.86	gold quality
tendon of biceps brachii	UBERON:0008188	55.95	gold quality
ectocervix	UBERON:0012249	55.15	gold quality
skin of hip	UBERON:0001554	55.05	silver quality
right lung	UBERON:0002167	54.98	gold quality
oviduct epithelium	UBERON:0004804	53.90	gold quality
placenta	UBERON:0001987	52.59	gold quality
lung	UBERON:0002048	52.48	gold quality
hair follicle	UBERON:0002073	52.43	gold quality
Brodmann (1909) area 46	UBERON:0006483	51.66	gold quality
pancreatic ductal cell	CL:0002079	51.50	silver quality
adenohypophysis	UBERON:0002196	51.02	gold quality
female reproductive system	UBERON:0000474	50.87	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	50.27	gold quality
endometrium	UBERON:0001295	50.13	gold quality
anatomical system	UBERON:0000467	50.08	gold quality
cervix epithelium	UBERON:0004801	50.08	gold quality
multicellular organism	UBERON:0000468	49.96	gold quality
material anatomical entity	UBERON:0000465	49.95	gold quality
epithelium of bronchus	UBERON:0002031	49.88	gold quality
epithelial cell of pancreas	CL:0000083	49.72	gold quality
bronchus	UBERON:0002185	49.66	gold quality
myocardium	UBERON:0002349	49.42	gold quality
trachea	UBERON:0003126	49.38	gold quality
blood vessel layer	UBERON:0004797	49.29	gold quality
quadriceps femoris	UBERON:0001377	49.28	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	6.18

HPA expression

RNA tissue specificity: Tissue enhanced

52 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Duodenum	tissue	47.9	medium
Small intestine	tissue	36.3	medium
Skin 1	tissue	31.4	low
Colon	tissue	19.6	not detected
Vagina	tissue	18.0	low
Stomach 1	tissue	16.7	low
Esophagus	tissue	11.7
Rectum	tissue	11.0	not detected
Pancreas	tissue	7.9	low
Urinary bladder	tissue	7.7	not detected
Salivary gland	tissue	6.9	low
Prostate	tissue	6.5	low
Liver	tissue	5.5	medium
Breast	tissue	4.1	low
Gallbladder	tissue	4.1	medium
Tonsil	tissue	3.8	not detected
Cervix	tissue	2.9	not detected
Appendix	tissue	2.9	not detected
Fallopian tube	tissue	2.3	medium
Seminal vesicle	tissue	2.2
Kidney	tissue	2.2	medium
Parathyroid gland	tissue	1.5	low
Thyroid gland	tissue	1.0	low
Endometrium 1	tissue	0.8	low
Lung	tissue	0.8	not detected
Medulla oblongata	tissue	0.6
Superior colliculi	tissue	0.6
Pituitary gland	tissue	0.5
Smooth muscle	tissue	0.5	not detected
Periaqueductal gray	tissue	0.4
Testis	tissue	0.3	high
Pons	tissue	0.3
Thalamus	tissue	0.3
Hypothalamus	tissue	0.3
Placenta	tissue	0.3	low
Spinal cord	tissue	0.3
Thymus	tissue	0.3
Midbrain	tissue	0.2
Substantia nigra	tissue	0.2
Retina	tissue	0.1
Adipose tissue	tissue	0.1	not detected
Skeletal muscle	tissue	0.1	low
Epididymis	tissue	0.1	low
Cerebellum	tissue	0.1	low
Hippocampus	tissue	0.1	low
Postcentral gyrus	tissue	0.1
Heart muscle	tissue	0.0	low
Cerebral cortex	tissue	0.0	low
Adrenal gland	tissue	0.0	medium
Nasopharynx	tissue	-1.0	high
Bronchus	tissue	-1.0	high
Oral mucosa	tissue	-1.0	low

Brain sub-regions (HPA Brain Atlas): detected in 156; highest nTPM — Centromedial thalamic nucleus (14.5), Globus pallidus, internus (13.8), Mammillary body (13.8), Cerebellar nuclei (13.7), Globus pallidus, externus (13.6).

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

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

5 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4283	100.00	66.42	2097
HSA-MIR-548AU-3P	99.70	68.22	1373
HSA-MIR-6512-3P	99.65	66.07	1468
HSA-MIR-6720-5P	99.65	66.22	1459
HSA-MIR-7154-3P	97.65	65.02	985

Functional genomics

gnomAD constraint: pLI 2.98e-13, LOEUF 1.06, missense Z -0.948 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD)

ENST00000647358 splits into 3 regions with different missense tolerance; 1 is missense-constrained (≈3% of the expected missense variation). Missense variants in a constrained region (low observed/expected) are more likely to be pathogenic. gnomAD

Region (GRCh38)	Missense obs / exp	o/e	Constrained
19:44,777,932–44,781,214	280 / 237.2	1.18	no
19:44,781,215–44,781,259	4 / 17.8	0.22	yes (p 1.0e-03)
19:44,781,260–44,800,440	371 / 370.8	1.00	no

Literature-anchored findings (GeneRIF, showing 15)

• Data demonstrate that two E3 ligases of different classes, CBLC and AIP4, can interact and cooperate to down-regulate EGFR signaling. (PMID:12226085)
• c-Cbl is a negative regulator of hepatocyte growth factor/receptor tyrosine kinase Met signaling in B cells, mediating ubiquitination and, consequently, proteosomal degradation of Met, with a role in Met-mediated tumorigenesis. (PMID:12244174)
• Src is a preferential target of Cbl-c for degradation (PMID:14661060)
• ubiquitin protein ligase activity is regulated in c-Cbl by phosphorylation-induced conformational change and constitutive activation by tyrosine to glutamate point mutations (PMID:15117950)
• the N terminus of Cbl-c contributes to the binding to the E2 and phosphorylation of Tyr-341 leads to a decrease in affinity and an increase in the E3 activity of Cbl-c (PMID:20525694)
• The ubiquitin ligase activity of Cbl-c by the direct interaction of the LIM zinc coordinating domain of Hic5 is demonstrated. (PMID:23145173)
• This retrospective multicentre study evaluates clinical, biochemical and genetic findings in 88 cblC patients (PMID:24599607)
• the effects of two pathogenic missense mutations on the the catalytic activities of the human B12-processing chaperone CblC (PMID:25809485)
• Silencing of CBLC causes increased sensitivity to PARP1 inhibitor olaparib in breast cancer cell line models and that defective homologous recombination (HR) DNA repair is the likely cause. (PMID:25883215)
• Data suggest that ubiquitin ligase CBLC controls mostly network organization of the Golgi Apparatus. (PMID:26393512)
• Methylmalonic aciduria with homocystinuria cblC is a multisystemic metabolic disease affecting cobalamin metabolism. The presence of retinal alterations in cblC is a common feature and it is reported to develop more frequently and into a more severe form in the early-onset phenotype, suggesting to some extent a correlation with the biochemical phenotype (PMID:28481040)
• ectopic expression of CBLC enhanced the activation of EGFR and downstream ERK1/2 signaling after ligand stimulation by competing with CBL for EGFR binding.. (PMID:29945960)
• Cbl-c is the most recently identified Cbl protein and is expressed exclusively in epithelial cells. Data mining reveals Cbl-c mutations associated with solid tumors. Subsequent cell-based analysis demonstrates a loss of E3 function and dominant negative effects for one of these mutations. (PMID:31260484)
• Stabilization of AURKA by the E3 ubiquitin ligase CBLC in lung adenocarcinoma. (PMID:35149839)
• CBLC inhibits the proliferation and metastasis of breast cancer cells via ubiquitination and degradation of CTTN. (PMID:36043996)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
mus_musculus	Cblc	ENSMUSG00000040525
rattus_norvegicus	Cblc	ENSRNOG00000018953
drosophila_melanogaster	Cbl	FBGN0020224
caenorhabditis_elegans		WBGENE00004829

Paralogs (2): CBL (ENSG00000110395), CBLB (ENSG00000114423)

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
Gallus gallus	Q98TY6	96.1%	Diamond
Xenopus tropicalis	Q6DFR2	94.3%	Diamond
Xenopus laevis	Q6NRE7	94.3%	Diamond
Cas NS-1 murine leukemia virus	P23092	99.4%	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
CEACAM16-AS1	ncRNA	107985305
CEACAM16	protein-coding	388551
BCL3	protein-coding	602
MIR8085	ncRNA	102465879
BCAM	protein-coding	4059
TOMM40	protein-coding	10452
NECTIN2	protein-coding	5819
APOE	protein-coding	348

Protein

Protein identifiers

E3 ubiquitin-protein ligase CBL-C — Q9ULV8 (reviewed: Q9ULV8)

Alternative names: RING finger protein 57, RING-type E3 ubiquitin transferase CBL-C, SH3-binding protein CBL-3, SH3-binding protein CBL-C, Signal transduction protein CBL-C

All UniProt accessions (2): A0A2R8Y647, Q9ULV8

UniProt curated annotations — full annotation on UniProt →

Function. Acts as an E3 ubiquitin-protein ligase, which accepts ubiquitin from specific E2 ubiquitin-conjugating enzymes, and then transfers it to substrates promoting their degradation by the proteasome. Functionally coupled with the E2 ubiquitin-protein ligases UB2D1, UB2D2 and UB2D3. Regulator of EGFR mediated signal transduction; upon EGF activation, ubiquitinates EGFR. Isoform 1, but not isoform 2, inhibits EGF stimulated MAPK1 activation. Promotes ubiquitination of SRC phosphorylated at ‘Tyr-419’. In collaboration with CD2AP may act as regulatory checkpoint for Ret signaling by modulating the rate of RET degradation after ligand activation; CD2AP converts it from an inhibitor to a promoter of RET degradation; the function limits the potency of GDNF on neuronal survival.

Subunit / interactions. Interacts with ubiquitin-conjugating enzyme E2 UBE2D2 and UBE2D3. Isoform 1 interacts with EGFR (tyrosine phosphorylated). Interacts with the SH3 domain proteins LYN and CRK. Interacts (via RING-type zinc finger) with TGFB1I1 (via LIM zinc-binding domain 2); the interaction is direct and enhances the E3 activity. Interacts directly with RET (inactive) and CD2AP; dissociates from RET upon RET activation by GDNF which also increases the interaction with CD2AP suggesting dissociation as CBLC:CD2AP complex. Interacts with SRC; the interaction is enhanced when SRC is phosphorylated at ‘Tyr-419’.

Tissue specificity. Ubiquitous.

Post-translational modifications. Phosphorylated on multiple tyrosine residues by SRC. Isoform 1, but not isoform 2, is phosphorylated on tyrosines by EGFR. Autoubiquitinated when phosphorylated at Tyr-341, enhanced by SRC; suggesting proteasomal degradation.

Activity regulation. Phosphorylation at Tyr-341 is necessary and sufficient for the activation of E3 activity.

Domain organisation. EF-hand-like and Sh2-like domains are required for N-terminal inhibition of E3 activity. The N-terminus is composed of the phosphotyrosine binding (PTB) domain, a short linker region and the RING-type zinc finger. The PTB domain, which is also called TKB (tyrosine kinase binding) domain, is composed of three different subdomains: a four-helix bundle (4H), a calcium-binding EF hand and a divergent SH2 domain. The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme.

Miscellaneous. This protein has one functional calcium-binding site.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9ULV8-1	1, Long	yes
Q9ULV8-2	2, Short

RefSeq proteins (2): NP_001124324, NP_036248* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001841	Znf_RING	Domain
IPR003153	Adaptor_Cbl_N_hlx	Domain
IPR011992	EF-hand-dom_pair	Homologous_superfamily
IPR013083	Znf_RING/FYVE/PHD	Homologous_superfamily
IPR014741	Adaptor_Cbl_EF_hand-like	Domain
IPR014742	Adaptor_Cbl_SH2-like	Domain
IPR017907	Znf_RING_CS	Conserved_site
IPR024159	Cbl_PTB	Domain
IPR024162	Adaptor_Cbl	Family
IPR036537	Adaptor_Cbl_N_dom_sf	Homologous_superfamily
IPR036860	SH2_dom_sf	Homologous_superfamily

Pfam: PF02262, PF02761, PF02762, PF13920

UniProt features (61 total): helix 18, mutagenesis site 12, strand 10, region of interest 6, binding site 4, sequence conflict 2, turn 2, chain 1, domain 1, modified residue 1, splice variant 1, sequence variant 1, zinc finger region 1, compositionally biased region 1

Structure

Experimental structures (PDB)

7 structures by resolution:

PDB	Title	Method	Resolution (Å)
3VRP	Crystal structure of the tyrosine kinase binding domain of Cbl-c in complex with …	X-RAY DIFFRACTION	1.52
3VRN	Crystal structure of the tyrosine kinase binding domain of Cbl-c	X-RAY DIFFRACTION	1.64
3VRO	Crystal structure of the tyrosine kinase binding domain of Cbl-c in complex with …	X-RAY DIFFRACTION	1.8
9OGW	Identification of ligands for E3 ligases using fragment-based methods	X-RAY DIFFRACTION	1.8
3VRR	Crystal structure of the tyrosine kinase binding domain of Cbl-c (PL mutant) in complex …	X-RAY DIFFRACTION	2
3VRQ	Crystal structure of the tyrosine kinase binding domain of Cbl-c (PL mutant)	X-RAY DIFFRACTION	2.39
3OP0	Crystal structure of Cbl-c (Cbl-3) TKB domain in complex with EGFR pY1069 peptide	X-RAY DIFFRACTION	2.52

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9ULV8-F1	80.85	0.54

Human Protein Atlas

Protein class: Enzymes, ENZYME proteins, Transferases, Metabolic proteins, Predicted intracellular proteins, Cancer-related genes

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): nucleoplasm; aggresome

Antibody reliability (HPA): IH approved · IF approved

Functional residue map

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

Ligand- & substrate-binding residues (4)

Position	Role
199	Ca(2+)
201	Ca(2+)
210	Ca(2+)
264	4-O-phospho-L-tyrosine

Post-translational modifications (1)

Type	Positions
Phosphotyrosine	341

Mutagenesis-validated functional residues (12)

Position	Phenotype
244	abolishes interaction with egfr. decreases interaction with src and abolishes src ubiquitination.
244	no effect on interaction with egfr and src as well as on src ubiquitination.
264	abolishes interaction with egfr. decreases interaction with src and abolishes src ubiquitination.
265	enhances interaction with egfr and src as well as src ubiquitination.
266	decreases interactions with egfr and src as well as src ubiquitination.
268	abolishes interaction with egfr. decreases interaction with and ubiquitination of src.
276	no effect on interaction with ret. binds slightly to src, this interaction is independent of src phosphorylation. strongly decreases src …
341	induces e3 activity and autoubiquitination. releases ubiquitin-conjugating enzyme e2 ube2d2 faster.
341	abolishes activation by egf stimulation and enhancement by tgfb1i1 of e3 activity.
341	abolishes e3 activity.
351	no effect on tgfb1i1 and src interactions. abolishes src ubiquitination. abolishes interaction with tgfb1i1; when associated with a-366 …
366	abolishes interaction with tgfb1i1. abolishes interaction with tgfb1i1; when associated with a-351.

Function

Pathways and Gene Ontology

Reactome pathways

0 curated (TAS) of 0; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

MSigDB gene sets: 111 (showing top): GSE45365_HEALTHY_VS_MCMV_INFECTION_CD8_TCELL_IFNAR_KO_UP, GOBP_NEGATIVE_REGULATION_OF_NEURON_APOPTOTIC_PROCESS, GOBP_REGULATION_OF_ERBB_SIGNALING_PATHWAY, GOBP_NEGATIVE_REGULATION_OF_ERBB_SIGNALING_PATHWAY, ROVERSI_GLIOMA_COPY_NUMBER_UP, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_NEGATIVE_REGULATION_OF_MAPK_CASCADE, GOBP_NEGATIVE_REGULATION_OF_INTRACELLULAR_SIGNAL_TRANSDUCTION, KEGG_ERBB_SIGNALING_PATHWAY, GOBP_ERBB_SIGNALING_PATHWAY, CHARAFE_BREAST_CANCER_BASAL_VS_MESENCHYMAL_UP, KEGG_PATHWAYS_IN_CANCER, GOBP_PROTEIN_STABILIZATION, GOBP_POST_TRANSLATIONAL_PROTEIN_MODIFICATION, GOBP_REGULATION_OF_PROTEIN_STABILITY

GO Biological Process (8): ubiquitin-dependent protein catabolic process (GO:0006511), signal transduction (GO:0007165), cell surface receptor signaling pathway (GO:0007166), protein ubiquitination (GO:0016567), negative regulation of epidermal growth factor receptor signaling pathway (GO:0042059), negative regulation of MAPK cascade (GO:0043409), regulation of signaling (GO:0023051), protein catabolic process (GO:0030163)

GO Molecular Function (11): phosphotyrosine residue binding (GO:0001784), epidermal growth factor receptor binding (GO:0005154), calcium ion binding (GO:0005509), zinc ion binding (GO:0008270), SH3 domain binding (GO:0017124), receptor tyrosine kinase binding (GO:0030971), ubiquitin protein ligase activity (GO:0061630), ubiquitin-protein transferase activity (GO:0004842), protein binding (GO:0005515), transferase activity (GO:0016740), metal ion binding (GO:0046872)

GO Cellular Component (2): plasma membrane (GO:0005886), membrane raft (GO:0045121)

GO top-level categories

34 GO namespaces:

Category	Terms
signaling	2
protein ubiquitination	1
modification-dependent protein catabolic process	1
cell communication	1
cellular process	1
regulation of cellular process	1
cellular response to stimulus	1
signal transduction	1
protein modification by small protein conjugation	1
epidermal growth factor receptor signaling pathway	1
regulation of epidermal growth factor receptor signaling pathway	1
negative regulation of ERBB signaling pathway	1
MAPK cascade	1
regulation of MAPK cascade	1
negative regulation of intracellular signal transduction	1
regulation of biological process	1
macromolecule catabolic process	1
protein metabolic process	1
protein phosphorylated amino acid binding	1
growth factor receptor binding	1
metal ion binding	1
transition metal ion binding	1
protein domain specific binding	1
signaling receptor binding	1
protein tyrosine kinase binding	1
ubiquitin-protein transferase activity	1
ubiquitin-like protein ligase activity	1
ubiquitin-like protein transferase activity	1
binding	1
catalytic activity	1
cation binding	1
membrane	1
cell periphery	1
membrane microdomain	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 8 of 21 annotations. The rest are phylogenetic / computational / electronic (IEA).

8 experimentally-supported GO terms:

GO term	NS	Evidence
negative regulation of MAPK cascade	BP	direct assay
negative regulation of epidermal growth factor receptor signaling pathway	BP	direct assay
protein ubiquitination	BP	direct assay
ubiquitin-dependent protein catabolic process	BP	direct assay
SH3 domain binding	MF	direct assay
epidermal growth factor receptor binding	MF	direct assay
phosphotyrosine residue binding	MF	direct assay
ubiquitin protein ligase activity	MF	direct assay

Protein interactions and networks

STRING

showing 15 of 456 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CBLC	CRK	P46108	473
CBLC	LYN	P07948	400
CBLC	FYN	P06241	330
CBLC	RNF223	E7ERA6	322
CBLC	ACVRL1	P37023	304
CBLC	AXDND1	Q5T1B0	275
CBLC	CBLL2	Q8N7E2	270
CBLC	ATP2C2	O75185	263
CBLC	EGFR	P00533	252
CBLC	CRKL	P46109	248
CBLC	CEACAM19	Q7Z692	244
CBLC	MMACHC	Q9Y4U1	242
CBLC	LIM2	P55344	241
CBLC	GRB2	P29354	241
CBLC	SH3KBP1	Q96B97	237

IntAct

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

27 partners by confidence:

Partner	Interaction type	MIscore	Records
ITCH	physical association	0.600	5
ATXN1	physical association	0.560	6
TARDBP	physical association	0.560	3
UBE2K	physical association	0.560	3
YES1	physical association	0.560	3
SHC1	physical association	0.550	1
GAK	association	0.530	2
MGME1	association	0.530	1
BAP1	physical association	0.490	2
CRK	physical association	0.490	2
ABI1	direct interaction	0.440	1
ALK	physical association	0.370	2
BIRC2	physical association	0.370	1
CHFR	physical association	0.370	1
HIP2	physical association	0.370	1
NACAD	physical association	0.370	1
OXA1L	physical association	0.370	1
SH3GL3	physical association	0.370	1
TRAF4	physical association	0.370	1
TRIM46	physical association	0.370	1
UBE2H	physical association	0.370	1
UBE2I	physical association	0.370	1
UBE2L3	physical association	0.370	1
UBE2L6	physical association	0.370	1
UBE2R2	physical association	0.370	1
TGFB1I1	association	0.350	1
SMAD4	proximity	0.270	4

BioGRID (116 interactions; top human partners by supporting records): EGFR (Affinity Capture-Western; 10 records), SRC (Affinity Capture-Western; 6 records), ITCH (Two-hybrid; 4 records), RET (Affinity Capture-Western; 4 records), CTTN (Affinity Capture-MS; 3 records), PDLIM7 (Two-hybrid; 3 records), TGFB1I1 (Affinity Capture-Western; 3 records), TWIST1 (Affinity Capture-Western; 3 records), ABI2 (Affinity Capture-MS; 2 records), BRK1 (Affinity Capture-MS; 2 records), CD2AP (Affinity Capture-Western; 2 records), CRK (Two-hybrid; 2 records), CYFIP1 (Affinity Capture-MS; 2 records), CYFIP2 (Affinity Capture-MS; 2 records), FYN (Affinity Capture-Western; 2 records)

SIGNOR signaling

10 signaling interactions:

A	Effect	B	Mechanism
ARHGEF7	down-regulates	CBLC	binding
CBLC	down-regulates	LRIG1	ubiquitination
LRIG1	up-regulates	CBLC	binding
INPPL1	down-regulates	CBLC	binding
SRC	up-regulates	CBLC	phosphorylation
Ub:E2	“up-regulates activity”	CBLC	ubiquitination
EPHB6	“up-regulates activity”	CBLC	binding
CBLC	“down-regulates quantity by destabilization”	RET	ubiquitination
SPRY2	down-regulates	CBLC
CBLC	“down-regulates quantity by destabilization”	EGFR	polyubiquitination

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 27 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 Receptor Tyrosine Kinases	5	12.9×	2e-03
Antigen processing: Ubiquitination & Proteasome degradation	6	11.2×	1e-03

GO biological processes:

GO term	Partners	Fold	FDR
protein modification process	5	47.0×	7e-06
protein polyubiquitination	7	31.1×	3e-07
ubiquitin-dependent protein catabolic process	9	25.7×	1e-08

Disease & clinical

Genetic variants

Variant evidence for CBLC: 94 ClinVar records (0 pathogenic / likely pathogenic); 1 CIViC cancer variant; 15 GWAS associations.

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	64
Likely benign	8
Benign	0

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 33 predictions of 809):

Position(s)	Effect	Δscore	Sites
19:44780903	acceptor_loss	1.0000	2
19:44781205–44781206	acceptor_loss	1.0000	6
19:44781370	donor_gain	1.0000
19:44790002–44790003	acceptor_loss	1.0000	5
19:44790092–44790093	donor_loss	1.0000	5
19:44792367	acceptor_gain	1.0000
19:44792375–44792377	acceptor_gain	1.0000	2
19:44792515–44792516	donor_loss	1.0000	5
19:44778285–44778286	donor_loss	0.9900	5
19:44780902	acceptor_gain	0.9900

AlphaMissense

645 missense substitutions predicted likely pathogenic (of 3,059 scored), across 182 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
F218	8	0.940	0.987
H368	8	0.930	0.978
F214	8	0.917	0.978
H235	8	0.880	0.977
D212	8	0.862	0.956
F175	8	0.818	0.935
C351	7	0.968	0.981
W273	7	0.965	0.995
F263	7	0.964	0.988
C386	7	0.952	0.978
C354	7	0.941	0.964
W228	7	0.937	0.977
C389	7	0.935	0.951
C366	7	0.930	0.957
F388	7	0.928	0.987
W160	7	0.926	0.974
C374	7	0.926	0.961
F211	7	0.924	0.967
C371	7	0.921	0.955
W221	7	0.903	0.978

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

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

2 prognostic cancer types:

Cancer	Prognostic	p-value
Kidney Renal Clear Cell Carcinoma (TCGA)	favorable	0.000126
Kidney Renal Papillary Cell Carcinoma (TCGA)	favorable	0.000922

Disease associations

OMIM: gene MIM:608453 | disease phenotypes:

GWAS associations

15 associations:

Study	Trait	p-value
GCST010243_185	Apolipoprotein B levels	0.000000e+00
GCST007827_3	Alzheimer’s disease or HDL levels (pleiotropy)	1e-97
GCST007827_5	Alzheimer’s disease or HDL levels (pleiotropy)	7e-74
GCST007827_6	Alzheimer’s disease or HDL levels (pleiotropy)	7e-54
GCST007827_7	Alzheimer’s disease or HDL levels (pleiotropy)	5e-50
GCST007827_8	Alzheimer’s disease or HDL levels (pleiotropy)	3e-36
GCST007848_3	LDL cholesterol	6e-30
GCST007320_101	Alzheimer’s disease or family history of Alzheimer’s disease	7e-25
GCST005952_8	Body mass index (age>50)	9e-12
GCST009496_8	Alzheimer’s disease (onset between ages 58 and 79)	3e-11
GCST005950_15	Body mass index x sex x age interaction (4df test)	2e-10
GCST005954_4	Body mass index x age interaction	2e-7
GCST006990_3	Cerebrospinal AB1-42 levels in Alzheimer’s disease dementia	3e-7
GCST005951_66	Body mass index	1e-6
GCST008152_195	Weight	9e-6

EFO canonical traits (from GWAS)

9 canonical traits:

EFO ID	Trait name
EFO:0004340	body mass index
EFO:0008007	age at assessment
EFO:0008343	sex interaction measurement
EFO:0004670	beta-amyloid 1-42 measurement
EFO:0009268	family history of Alzheimer’s disease
EFO:0004612	high density lipoprotein cholesterol measurement
EFO:0004611	low density lipoprotein cholesterol measurement
EFO:0004338	body weight
EFO:0004615	apolipoprotein B measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5724772 (SINGLE PROTEIN)

Clinical evidence (CIViC)

Drug × variant × indication, from 1 curated evidence items. CIViC evidence level: A (validated) → B (clinical) → C (case study) → D (preclinical) → E (inferential).

1 predictive associations by evidence level:

Variant	Therapy	Indication	Effect	Level	CIViC
CBLC EXPRESSION	Olaparib	Breast Carcinoma	Resistance	CIViC D	EID805

CIViC curated variants (1)

Named clinical variants curated in CIViC for this gene (the catalogue beneath the predictive evidence above):

EXPRESSION.

PharmGKB: 1 entry (CPIC guideline: no)

Binding affinities (BindingDB)

1009 measured of 1011 human assays (1209 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
4-(difluoromethyl)-2-(6-(ethylamino)-4- ((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4- triazol-3-yl)cyclobutyl)pyridin-2-yl)-6-(((1- methylcyclobutyl)amino)methyl)isoindolin- 1-one	KD	0.1 nM	US-12187709: Lactams as CBL-B inhibitors selective over C-CBL
4-chloro-2-(3-((1s,3S)-3-fluoro-1-(4- methyl-4H-1,2,4-triazol-3- yl)cyclobutyl)phenyl)-6-((R)-1-((1- methylcyclobutyl)amino)ethyl)isoindolin-1- one	KD	0.1 nM	US-12187709: Lactams as CBL-B inhibitors selective over C-CBL
4-chloro-2-(3-((1r,3R)-3-fluoro-1-(4- methyl-4H-1,2,4-triazol-3- yl)cyclobutyl)phenyl)-6-((R)-1-((1- methylcyclobutyl)amino)ethyl)isoindolin-1- one	KD	0.1 nM	US-12187709: Lactams as CBL-B inhibitors selective over C-CBL
2-(3-(ethylamino)-5-((1r,3r)-3-methyl-1-(4- methyl-4H-1,2,4-triazol-3- yl)cyclobutyl)phenyl)-6-(((1- methylcyclobutyl)amino)methyl)-4- (trifluoromethyl)isoindolin-1-one	KD	0.2 nM	US-12187709: Lactams as CBL-B inhibitors selective over C-CBL
2-(3-((R)-(4-methyl-4H-1,2,4-triazol-3- yl)(oxetan-3-yl)methyl)phenyl)-6-((S)-1-((1- methylcyclobutyl)amino)propyl)-4- (trifluoromethyl)isoindolin-1-one	KD	0.2 nM	US-12187709: Lactams as CBL-B inhibitors selective over C-CBL
(S)-2-(3-(cyclobutyl(4-methyl-4H-1,2,4- triazol-3-yl)methyl)phenyl)-6-(((1- methylcyclobutyl)amino)methyl)-4- (trifluoromethyl)isoindolin-1-one	KD	0.22 nM	US-12187709: Lactams as CBL-B inhibitors selective over C-CBL
2-(6-(cyclobutylamino)-4-((1R,3R)-3- methyl-1-(4-methyl-4H-1,2,4-triazol-3- yl)cyclobutyl)pyridin-2-yl)-6-(((1- methylcyclobutyl)amino)methyl)-4- (trifluoromethyl)isoindolin-1-one	KD	0.24 nM	US-12187709: Lactams as CBL-B inhibitors selective over C-CBL
2-(6-cyclopropyl-4-(3,3-difluoro-1-(4- methyl-4H-1,2,4-triazol-3- yl)cyclobutyl)pyridin-2-yl)-6-(((1- methylcyclobutyl)amino)methyl)-4- (trifluoromethyl)isoindolin-1-one	KD	0.25 nM	US-12187709: Lactams as CBL-B inhibitors selective over C-CBL
4-chloro-2-(3-((1r,3r)-3-chloro-1-(4-methyl- 4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-6- (((1-methylcyclobutyl)amino)- methyl)isoindolin-1-one	KD	0.25 nM	US-12187709: Lactams as CBL-B inhibitors selective over C-CBL
2-(3-((1r,3r)-3-chloro-1-(4-methyl-4H- 1,2,4-triazol-3-yl)cyclobutyl)phenyl)-6-(((1- methylcyclobutyl)amino)methyl)-4- (trifluoromethyl)isoindolin-1-one hydrochloride	KD	0.27 nM	US-12187709: Lactams as CBL-B inhibitors selective over C-CBL
2-(3-(ethylamino)-5-((1s,3s)-3-methyl-1-(4- methyl-4H-1,2,4-triazol-3- yl)cyclobutyl)phenyl)-6-(((1- methylcyclobutyl)amino)methyl)-4- (trifluoromethyl)isoindolin-1-one	KD	0.3 nM	US-12187709: Lactams as CBL-B inhibitors selective over C-CBL
2-(3-((R)-((1s,3S)-3-fluorocyclobutyl)(4- methyl-4H-1,2,4-triazol-3- yl)methyl)phenyl)-6-(((1- methylcyclobutyl)amino)methyl)-4- (trifluoromethyl)isoindolin-1-one	KD	0.3 nM	US-12187709: Lactams as CBL-B inhibitors selective over C-CBL
(S)-6-(2-hydroxy-1-((1- methylcyclobutyl)amino)ethyl)-2-(3-(1-(4- methyl-4H-1,2,4-triazol-3- yl)cyclobutyl)phenyl)-4- (trifluoromethyl)isoindolin-1-one	KD	0.3 nM	US-12187709: Lactams as CBL-B inhibitors selective over C-CBL
2-(3-ethoxy-5-((1r,3r)-3-methyl-1-(4- methyl-4H-1,2,4-triazol-3- yl)cyclobutyl)phenyl)-6-(((1- methylcyclobutyl)amino)methyl)-4- (trifluoromethyl)isoindolin-1-one	KD	0.3 nM	US-12187709: Lactams as CBL-B inhibitors selective over C-CBL
(R)-3-((4-(6-(4-methyl-4H-1,2,4-triazol-3- yl)-2-oxaspiro[3.3]heptan-6-yl)-6-(6-(((1- methylcyclobutyl)amino)methyl)-1-oxo-4- (trifluoromethyl)isonidolin-2-yl)pyridin-2- yl)amino)butanenitrile	KD	0.3 nM	US-12187709: Lactams as CBL-B inhibitors selective over C-CBL
4-(difluoromethyl)-2-(3-((R)-(4-methyl-4H- 1,2,4-triazol-3-yl)(oxetan-3- yl)methyl)phenyl)-6-((S)-1-((1- methylcyclobutyl)amino)ethyl)isoindolin-1- one	KD	0.3 nM	US-12187709: Lactams as CBL-B inhibitors selective over C-CBL
2-(3-((1r,3r)-3-chloro-1-(4-methyl-4H- 1,2,4-triazol-3-yl)cyclobutyl)phenyl)-4- (difluoromethyl)-6-(((1- methylcyclobutyl)amino)methyl)isoindolin- 1-one	KD	0.3 nM	US-12187709: Lactams as CBL-B inhibitors selective over C-CBL
2-(4-(3,3-difluoro-1-(4-methyl-4H-1,2,4- triazol-3-yl)cyclobutyl)-6-ethoxypyridin-2- yl)-6-(((1-methylcyclobutyl)amino)methyl)- 4-(trifluoromethyl)isoindolin-1-one	KD	0.35 nM	US-12187709: Lactams as CBL-B inhibitors selective over C-CBL
6-((((S)-1-cyclobutylethyl)amino)methyl)-2- (3-((1r,3S)-3-methoxy-1-(4-methyl-4H- 1,2,4-triazol-3-yl)cyclobutyl)phenyl)-4- (trifluoromethyl)isoindolin-1-one	KD	0.35 nM	US-12187709: Lactams as CBL-B inhibitors selective over C-CBL
2-(6-(cyclobutylamino)-4-((1S,3S)-3- methyl-1-(4-methyl-4H-1,2,4-triazol-3- yl)cyclobutyl)pyridin-2-yl)-6-(((1- methylcyclobutyl)amino)methyl)-4- (trifluoromethyl)isoindolin-1-one	KD	0.36 nM	US-12187709: Lactams as CBL-B inhibitors selective over C-CBL
2-(4-(3,3-difluoro-1-(4-methyl-4H-1,2,4- triazol-3-yl)cyclobutyl)-6- (ethylamino)pyridin-2-yl)-6-(((1- methylcyclobutyl)amino)methyl)-4- (trifluoromethyl)isoindolin-1-one	KD	0.37 nM	US-12187709: Lactams as CBL-B inhibitors selective over C-CBL
2-(3-ethoxy-5-((1s,3s)-3-methyl-1-(4- methyl-4H-1,2,4-triazol-3- yl)cyclobutyl)phenyl)-6-(((1- methylcyclobutyl)amino)methyl)-4- (trifluoromethyl)isoindolin-1-one	KD	0.37 nM	US-12187709: Lactams as CBL-B inhibitors selective over C-CBL
2-(6-(cyclopentyloxy)-4-((1S,3R)-3-methyl- 1-(4-methyl-4H-1,2,4-triazol-3- y)cyclobutyl)pyridin-2-yl)-6-(((S)-2- isopropyl-4-methylpiperazin-1-yl)methyl)- 4-(trifluoromethyl)isoindolin-1-one	KD	0.4 nM	US-12187709: Lactams as CBL-B inhibitors selective over C-CBL
(R)-2-(3-(3,3-difluoro-1-(4-methyl-4H- 1,2,4-triazol-3-yl)cyclobutyl)phenyl)-6-(1- ((1-methylcyclobutyl)amino)ethyl)-4- (trifluoromethyl)isoindolin-1-one	KD	0.4 nM	US-12187709: Lactams as CBL-B inhibitors selective over C-CBL
4-chloro-2-(3-((S)-((1r,3S)-3- fluorocyclobutyl)(4-methyl-4H-1,2,4-triazol- 3-yl)methyl)phenyl)-6-(((1- methylcyclobutyl)amino)methyl)isoindolin- 1-one	KD	0.4 nM	US-12187709: Lactams as CBL-B inhibitors selective over C-CBL
2-(3-((R)-((1s,3S)-3-chlorocyclobutyl)(4- methyl-4H-1,2,4-triazol-3- yl)phenyl)phenyl)-6-(((1- methylcyclobutyl)amino)methyl)-4- (trifluoromethyl)isoindolin-1-one	KD	0.4 nM	US-12187709: Lactams as CBL-B inhibitors selective over C-CBL
(S)-4-chloro-2-(3-(1-(4-methyl-4H-1,2,4- triazol-3-yl)propyl)phenyl)-6-(((1- methylcyclobutyl)amino)methyl)isoindolin- 1-one	KD	0.4 nM	US-12187709: Lactams as CBL-B inhibitors selective over C-CBL
6-((R)-cyclopropyl((1- methylcyclobutyl)amino)methyl)-2-(3-((R)- (4-methyl-4H-1,2,4-triazol-3-yl)(oxetan-3- yl)methyl)phenyl)-4- (trifluoromethyl)isoindolin-1-one	KD	0.4 nM	US-12187709: Lactams as CBL-B inhibitors selective over C-CBL
6-((R)-cyclobutyl((1- methylcyclobutyl)amino)methyl)-2-(3-((R)- (4-methyl-4H-1,2,4-triazol-3-yl)(oxetan-3- yl)methyl)phenyl)-4- (trifluoromethyl)isoindolin-1-one	KD	0.4 nM	US-12187709: Lactams as CBL-B inhibitors selective over C-CBL
2-(3-((R)-(4-methyl-4H-1,2,4-triazol-3- yl)(oxetan-3-yl)methyl)phenyl)-6-((R)-1- ((1-methylcyclobutyl)amino)ethyl)-4- (trifluoromethyl)isoindolin-1-one	KD	0.4 nM	US-12187709: Lactams as CBL-B inhibitors selective over C-CBL
2-(3-((1r,3R)-3-methoxy-1-(4-methyl-4H- 1,2,4-triazol-3-yl)cyclobutyl)phenyl)-6-((R)- 1-((1-methylcyclobutyl)amino)ethyl)-4- (trifluoromethyl)isoindolin-1-one	KD	0.42 nM	US-12187709: Lactams as CBL-B inhibitors selective over C-CBL
2-(3-((1r,3r)-1-(4-methyl-4H-1,2,4-triazol- 3-yl)-3-(methylthio)cyclobutyl)phenyl)-6- (((1-methylcyclobutyl)amino)methyl)-4- (trifluoromethyl)isoindolin-1-one	KD	0.47 nM	US-12187709: Lactams as CBL-B inhibitors selective over C-CBL
2-(3-((1r,3r)-3-methyl-1-(4-methyl-4H- 1,2,4-triazol-3-yl)cyclobutyl)phenyl)-6-(((1- methylcyclobutyl)amino)methyl)-4- (trifluoromethyl)isoindolin-1-one	KD	0.5 nM	US-12187709: Lactams as CBL-B inhibitors selective over C-CBL
(R)-2-(3-(cyclopropyl(4-methyl-4H-1,2,4- triazol-3-yl)methyl)phenyl)-6-(((1- methylcyclobutyl)amino)methyl)-4- (trifluoromethyl)isoindolin-1-one	KD	0.5 nM	US-12187709: Lactams as CBL-B inhibitors selective over C-CBL
4-(difluoromethyl)-2-(3-((R)-((1s,3S)-3- fluorocyclobutyl)(4-methyl-4H-1,2,4-triazol- 3-yl)methyl)phenyl)-6-(((1- methylcyclobutyl)amino)methyl)isoindolin- 1-one	KD	0.5 nM	US-12187709: Lactams as CBL-B inhibitors selective over C-CBL
2-(3-((1s,3s)-1-(4-methyl-4H-1,2,4-triazol- 3-yl)-3-(methylthio)cyclobutyl)phenyl)-6- (((1-methylcyclobutyl)amino)methyl)-4- (trifluoromethyl)isoindolin-1-one	KD	0.57 nM	US-12187709: Lactams as CBL-B inhibitors selective over C-CBL
2-((1r,3r)-3-(4-methyl-4H-1,2,4-triazol-3- yl)-3-(3-(6-(((1- methylcyclobutyl)amino)methyl)-1-oxo-4- (trifluoromethyl)isoindolin-2- yl)phenyl)cyclobutyl)acetonitrile	KD	0.6 nM	US-12187709: Lactams as CBL-B inhibitors selective over C-CBL
2-(3-((S)-((1s,3R)-3- (difluoromethoxy)cyclobutyl)(4-methyl-4H- 1,2,4-triazol-3-yl)methyl)phenyl)-6-(((1- methylcyclobutyl)amino)methyl)-4- (trifluoromethyl)isoindolin-1-one	KD	0.6 nM	US-12187709: Lactams as CBL-B inhibitors selective over C-CBL
(S)-2-(3-(cyclopentyl(4-methyl-4H-1,2,4- triazol-3-yl)methyl)phenyl)-6-(((1- methylcyclobutyl)amino)methyl)-4- (trifluoromethyl)isoindolin-1-one	KD	0.65 nM	US-12187709: Lactams as CBL-B inhibitors selective over C-CBL
(R)-2-(3-(1-fluoro-1-(4-methyl-4H-1,2,4- triazol-3-yl)propyl)phenyl)-6-(((1- methylcyclobutyl)amino)methyl)-4- (trifluoromethyl)isoindolin-1-one	KD	0.65 nM	US-12187709: Lactams as CBL-B inhibitors selective over C-CBL
2-(6-(cyclopentylamino)-4-((1s,3s)-3- methyl-1-(4-methyl-4H-1,2,4-triazol-3- yl)cyclobutyl)pyridin-2-yl)-6-(((1- methylcyclobutyl)amino)methyl)-4- (trifluoromethyl)isoindolin-1-one	KD	0.7 nM	US-12187709: Lactams as CBL-B inhibitors selective over C-CBL
2-(3-((4-methyl-4H-1,2,4-triazol-3- yl)(oxetan-3-yl)ethyl)phenyl)-6-((S)-1-((1- methylcyclobutyl)amino)methyl)-4- (trifluoromethyl)isoindolin-1-one	KD	0.7 nM	US-12187709: Lactams as CBL-B inhibitors selective over C-CBL
4-chloro-2-(3-((1s,3s)-3-chloro-1-(4- methyl-4H-1,2,4-triazol-3- yl)cyclobutyl)phenyl)-6-(((1- methylcyclobutyl)amino)methyl)isoindolin- 1-one	KD	0.7 nM	US-12187709: Lactams as CBL-B inhibitors selective over C-CBL
(S)-6-(1-(cyclobutylamino)ethyl)-2-(3-(3,3- difluoro-1-(4-methyl-4H-1,2,4-triazol-3- yl)cyclobutyl)phenyl)-4- (trifluoromethyl)isoindolin-1-one	KD	0.8 nM	US-12187709: Lactams as CBL-B inhibitors selective over C-CBL
(R)-2-(3-((3-fluorooxetan-3-yl)(4-methyl- 4H-1,2,4-triazol-3-yl)methyl)phenyl)-6-(((1- methylcyclobutyl)amino)methyl)-4- (trifluoromethyl)isoindolin-1-one	KD	0.8 nM	US-12187709: Lactams as CBL-B inhibitors selective over C-CBL
2-(3-((1s,3s)-3-(fluoromethyl)-1-(4-methyl- 4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-6- (((1-methylcyclobutyl)amino)methyl)-4- (trifluoromethyl)isoindolin-1-one	KD	0.83 nM	US-12187709: Lactams as CBL-B inhibitors selective over C-CBL
2-(3-((1r,3r)-3-(fluoromethyl)-1-(4-methyl- 4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-6- (((1-methylcyclobutyl)amino)methyl)-4- (trifluoromethyl)isoindolin-1-one	KD	0.85 nM	US-12187709: Lactams as CBL-B inhibitors selective over C-CBL
2-(3-((1r,3r)-3-(difluoromethoxy)-1-(4- methyl-4H-1,2,4-triazol-3- yl)cyclobutyl)phenyl)-6-(((1- methylcyclobutyl)amino)methyl)-4- (trifluoromethyl)isoindolin-1-one	KD	0.85 nM	US-12187709: Lactams as CBL-B inhibitors selective over C-CBL
2-((1S,3s)-3-((R)-(4-methyl-4H-1,2,4- triazol-3-yl)(3-(6-(((1- methylcyclobutyl)amino)methyl)-1-oxo-4- (trifluoromethyl)isoindolin-2- yl)phenyl)methyl)cyclobutyl)acetonitrile	KD	0.85 nM	US-12187709: Lactams as CBL-B inhibitors selective over C-CBL

ChEMBL bioactivities

7 potent at pChembl≥5 of 7 total, top 7 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.10	IC50	8	nM	CHEMBL5593645
8.00	IC50	10	nM	CHEMBL5568649
7.52	IC50	30	nM	CHEMBL5565433
7.40	IC50	40	nM	CHEMBL5568870
6.96	IC50	110	nM	CHEMBL5562897
6.68	Kd	210	nM	CHEMBL5563408
6.66	IC50	220	nM	CHEMBL5592177

PubChem BioAssay actives

8 with measured affinity, of 9 total; 8 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
6-cyclopropyl-N-[3-[3,3-difluoro-1-[(R)-fluoro-(4-methyl-1,2,4-triazol-3-yl)methyl]cyclobutyl]phenyl]-4-[[(2S)-4-methyl-2-propan-2-ylpiperazin-1-yl]methyl]pyridine-2-carboxamide	2107202: Inhibition of c-Cbl (unknown origin) by HTRF method	ic50	0.0080	uM
N-[3-[3-(cyanomethyl)-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]phenyl]-6-[[(3S)-3-(difluoromethyl)piperidin-1-yl]methyl]imidazo[1,2-a]pyridine-8-carboxamide	2107207: Inhibition of c-Cbl (unknown origin) expressed in Escherichia coli measured for 90 mins by HTRF method	ic50	0.0100	uM
3-[3-[3-methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]phenyl]-1-[(1S)-1-(1-methylpyrazol-4-yl)ethyl]-5-(trifluoromethyl)pyridin-2-one	2107205: Inhibition of c-Cbl (unknown origin) by TR-FRET assay	ic50	0.0300	uM
N-[3-[3-(cyanomethyl)-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]phenyl]-7-[1-[(3S)-3-methylpiperidin-1-yl]ethyl]-1H-pyrrolo[3,2-b]pyridine-5-carboxamide	2107207: Inhibition of c-Cbl (unknown origin) expressed in Escherichia coli measured for 90 mins by HTRF method	ic50	0.0400	uM
2-[3-(cyclopentylamino)-5-[3,3-difluoro-1-[(4-methyl-1,2,4-triazol-3-yl)methyl]cyclobutyl]phenyl]-6-[[(1-methylcyclobutyl)amino]methyl]-4-(trifluoromethyl)-3H-isoindol-1-one	2098225: Inhibition of C-Cbl (unknown origin) by TR-FRET assay	ic50	0.1100	uM
4-[2-cyclopropyl-6-[5-[[(1-fluorocyclobutyl)methylamino]methyl]-3-oxo-7-(trifluoromethyl)-1H-isoindol-2-yl]-4-pyridinyl]-3-(4-methyl-1,2,4-triazol-3-yl)benzonitrile	2107202: Inhibition of c-Cbl (unknown origin) by HTRF method	ic50	0.2000	uM
6-[[[1-(methoxymethyl)cyclopropyl]amino]methyl]-2-[3-[3-methoxy-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]phenyl]-4-(trifluoromethyl)-3H-isoindol-1-one	2107203: Binding affinity to c-Cbl (unknown origin) assessed as dissociation constant by SPR assay	kd	0.2100	uM
6-[(2,2-difluoro-5-azaspiro[2.3]hexan-5-yl)methyl]-2-[3-[3-[(S)-fluoro-(4-methyl-1,2,4-triazol-3-yl)methyl]oxetan-3-yl]phenyl]-4-(trifluoromethyl)-3H-isoindol-1-one	2098225: Inhibition of C-Cbl (unknown origin) by TR-FRET assay	ic50	0.2200	uM

CTD chemical–gene interactions

21 total (human), top 21 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	increases expression, decreases expression, decreases methylation	3
entinostat	increases expression, affects cotreatment	2
Panobinostat	affects cotreatment, increases expression	2
bisphenol A	decreases expression	1
benzo(e)pyrene	decreases methylation	1
cupric chloride	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
ICG 001	decreases expression	1
dorsomorphin	increases expression, affects cotreatment	1
Acetaminophen	increases expression	1
Benzo(a)pyrene	decreases methylation	1
Caffeine	decreases phosphorylation	1
Estradiol	affects cotreatment, decreases expression	1
Methapyrilene	decreases methylation	1
Progesterone	decreases expression	1
Smoke	increases expression	1
Thiram	decreases expression	1
Tobacco Smoke Pollution	increases expression	1
Valproic Acid	increases expression	1
Aflatoxin B1	decreases expression	1
Cadmium Chloride	decreases expression	1

ChEMBL screening assays

5 unique, capped per target: 5 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5539983	Binding	Inhibition of C-Cbl (unknown origin) by TR-FRET assay	Rising Star in Immunotherapy: Development and Therapeutic Potential of Small-Molecule Inhibitors Targeting Casitas B Cell Lymphoma-b (Cbl-b). — *J Med Chem*

Cellosaurus cell lines

3 cell lines: 3 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D1LX	Abcam K-562 CBLC KO	Cancer cell line	Female
CVCL_D2IH	Abcam Raji CBLC KO	Cancer cell line	Male
CVCL_UQ29	Abcam Jurkat CBLC KO	Cancer cell line	Male

Clinical trials (associated diseases)

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

Predicted chemistry — Sugi Predict

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