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 Cancer (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

• Clinical variants (ClinVar): 94 total
• Druggable target: yes
• Precision-oncology evidence (CIViC): 1 curated variant–drug association
• 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: 15 — 14 protein_coding, 1 nonsense_mediated_decay

ENST00000341505, ENST00000647063, ENST00000647358, ENST00000880087, ENST00000880088, ENST00000880089, ENST00000880090, ENST00000880091, ENST00000880092, ENST00000880093, ENST00000880094, ENST00000880095, ENST00000880096, ENST00000880097, ENST00000916799

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.

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

271 total, 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

Single-cell (SCXA)

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

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

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

5 targeting CBLC, 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-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

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)

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): Q9ULV8, A0A2R8Y647

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 (59 total): helix 16, 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.

PDB	Method	Resolution (Å)
3VRP	X-RAY DIFFRACTION	1.52
3VRN	X-RAY DIFFRACTION	1.64
3VRO	X-RAY DIFFRACTION	1.8
9OGW	X-RAY DIFFRACTION	1.8
3VRR	X-RAY DIFFRACTION	2
3VRQ	X-RAY DIFFRACTION	2.39
3OP0	X-RAY DIFFRACTION	2.52

Predicted structure (AlphaFold)

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

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): 199; 201; 210; 264

Post-translational modifications (1): 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. strong
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 associ
366	abolishes interaction with tgfb1i1. abolishes interaction with tgfb1i1; when associated with a-351.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

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 (11): 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), negative regulation of neuron apoptotic process (GO:0043524), protein stabilization (GO:0050821), response to glial cell derived neurotrophic factor (GO:1990790), 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

Rollup of top GO terms by namespace:

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
negative regulation of apoptotic process	1
regulation of neuron apoptotic process	1
neuron apoptotic process	1
regulation of protein stability	1
response to growth factor	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

Protein interactions and networks

STRING

586 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CBLC	UBE2U	Q5VVX9	543
CBLC	CRK	P46108	499
CBLC	LYN	P07948	417
CBLC	RNF223	E7ERA6	377
CBLC	CBLL2	Q8N7E2	372
CBLC	ZNF462	Q96JM2	348
CBLC	FYN	P06241	345
CBLC	GRB2	P29354	306
CBLC	ATP2C2	O75185	303
CBLC	EGFR	P00533	302
CBLC	RNF39	Q9H2S5	290
CBLC	CRKL	P46109	289
CBLC	SH3KBP1	Q96B97	285
CBLC	VAV1	P15498	281
CBLC	TRIM72	Q6ZMU5	279

IntAct

63 interactions, top by confidence:

A	B	Type	Score
CBLC	ITCH	psi-mi:“MI:0915”(physical association)	0.600
CBLC	ITCH	psi-mi:“MI:0403”(colocalization)	0.600
ITCH	CBLC	psi-mi:“MI:0915”(physical association)	0.600
YES1	CBLC	psi-mi:“MI:0915”(physical association)	0.560
CBLC	UBE2K	psi-mi:“MI:0915”(physical association)	0.560
ATXN1	CBLC	psi-mi:“MI:0915”(physical association)	0.560
TARDBP	CBLC	psi-mi:“MI:0915”(physical association)	0.560
CBLC	SHC1	psi-mi:“MI:0915”(physical association)	0.550
CBLC	GAK	psi-mi:“MI:0914”(association)	0.530
CBLC	MGME1	psi-mi:“MI:0914”(association)	0.530
	INPPL1	psi-mi:“MI:0914”(association)	0.500
CRK	CBLC	psi-mi:“MI:0915”(physical association)	0.490
CBLC	BAP1	psi-mi:“MI:0915”(physical association)	0.490

BioGRID (116): CBLC (Two-hybrid), ABI2 (Affinity Capture-MS), WASF1 (Affinity Capture-MS), BRK1 (Affinity Capture-MS), NCKAP1 (Affinity Capture-MS), WASF2 (Affinity Capture-MS), LPP (Affinity Capture-MS), ZNHIT2 (Affinity Capture-MS), CYFIP2 (Affinity Capture-MS), GAK (Affinity Capture-MS), CYFIP1 (Affinity Capture-MS), MGME1 (Affinity Capture-MS), BAP1 (Two-hybrid), EGFR (Affinity Capture-Western), CBLC (Affinity Capture-Western)

ESM2 similar proteins: A0A8C2M425, A1L1J9, A1L504, A6NH21, A8WCG0, B0BNG2, F1RMN2, O43292, O75908, O76062, O77759, O88496, O88908, O89109, P38435, Q07175, Q0P4Y8, Q49LS0, Q5KR61, Q5RF50, Q5XK03, Q5ZKZ9, Q643R3, Q658P3, Q6MG14, Q6NVG1, Q767L9, Q7TN60, Q7TPN3, Q7TQM4, Q7ZWN0, Q8BKF1, Q8C3X8, Q8IUH8, Q8IZY2, Q8N130, Q8VC65, Q8WMV1, Q91YD1, Q9BU23

Diamond homologs: G3V8H4, P22681, P22682, P23092, Q13191, Q3TTA7, Q6DFR2, Q6GQL0, Q6NRE7, Q80XL1, Q8K4S7, Q9ULV8, O60683, Q09463, Q54S31, Q8HXW8, Q9FNI6

SIGNOR signaling

10 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 32 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	11.2×	3e-03
Antigen processing: Ubiquitination & Proteasome degradation	6	9.7×	2e-03

GO biological processes:

GO term	Partners	Fold	FDR
protein modification process	5	42.1×	1e-05
protein polyubiquitination	7	27.9×	8e-07
ubiquitin-dependent protein catabolic process	9	23.0×	4e-08

Disease & clinical

Cancer significance

Clinical variants and AI predictions

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

Top pathogenic / likely-pathogenic (0)

SpliceAI

1565 predictions. Top by Δscore:

Variant	Effect	Δscore
19:44780903:A:AG	acceptor_gain	1.0000
19:44780903:AG:A	acceptor_gain	1.0000
19:44780903:AGGC:A	acceptor_gain	1.0000
19:44780904:G:GA	acceptor_gain	1.0000
19:44780904:GG:G	acceptor_gain	1.0000
19:44780904:GGC:G	acceptor_gain	1.0000
19:44780904:GGCG:G	acceptor_gain	1.0000
19:44781047:GCCCG:G	donor_gain	1.0000
19:44781052:G:GG	donor_gain	1.0000
19:44781056:G:GG	donor_gain	1.0000
19:44781203:CCAGG:C	acceptor_loss	1.0000
19:44781204:CAGG:C	acceptor_loss	1.0000
19:44781205:AGG:A	acceptor_loss	1.0000
19:44781206:G:A	acceptor_loss	1.0000
19:44781206:GGT:G	acceptor_gain	1.0000
19:44781206:GGTGT:G	acceptor_gain	1.0000
19:44781370:G:T	donor_gain	1.0000
19:44784394:G:GT	donor_gain	1.0000
19:44784397:GGCTT:G	donor_gain	1.0000
19:44784398:GCTT:G	donor_gain	1.0000
19:44784398:GCTTG:G	donor_gain	1.0000
19:44784402:G:GG	donor_gain	1.0000
19:44790000:CCA:C	acceptor_loss	1.0000
19:44790002:A:AC	acceptor_loss	1.0000
19:44790002:A:AG	acceptor_gain	1.0000
19:44790003:G:GG	acceptor_gain	1.0000
19:44790003:GCT:G	acceptor_gain	1.0000
19:44790003:GCTA:G	acceptor_gain	1.0000
19:44790003:GCTAC:G	acceptor_gain	1.0000
19:44790087:CAGAG:C	donor_loss	1.0000

AlphaMissense

3059 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
19:44784301:T:A	W273R	0.995
19:44784301:T:C	W273R	0.995
19:44784280:A:C	S266R	0.989
19:44784282:C:A	S266R	0.989
19:44784282:C:G	S266R	0.989
19:44784272:T:C	F263S	0.988
19:44784303:G:C	W273C	0.988
19:44784303:G:T	W273C	0.988
19:44781358:T:C	F218L	0.987
19:44781360:T:A	F218L	0.987
19:44781360:T:G	F218L	0.987
19:44784265:T:G	Y261D	0.987
19:44793498:T:C	F388L	0.987
19:44793500:C:A	F388L	0.987
19:44793500:C:G	F388L	0.987
19:44784271:T:C	F263L	0.985
19:44784273:C:A	F263L	0.985
19:44784273:C:G	F263L	0.985
19:44792454:G:C	K359N	0.982
19:44792454:G:T	K359N	0.982
19:44782422:G:A	G237D	0.981
19:44792428:T:A	C351S	0.981
19:44792428:T:C	C351R	0.981
19:44792429:G:C	C351S	0.981
19:44784304:G:C	A274P	0.980
19:44792429:G:A	C351Y	0.979
19:44792430:C:G	C351W	0.979
19:44781346:T:C	F214L	0.978
19:44781348:C:A	F214L	0.978
19:44781348:C:G	F214L	0.978

dbSNP variants (sampled 300 via entrez): RS1000151116 (19:44783862 C>T), RS1000593338 (19:44778172 C>G,T), RS1000666675 (19:44777999 G>T), RS1000690482 (19:44798287 C>G), RS1000755141 (19:44792976 G>A), RS1000799855 (19:44784966 T>G), RS1000848555 (19:44793233 T>C), RS1000856224 (19:44790656 G>A), RS1000955289 (19:44787204 T>A), RS1001058255 (19:44796344 G>A,T), RS1001168415 (19:44784881 A>G,T), RS1001180280 (19:44789464 C>T), RS1001244785 (19:44794036 T>G), RS1001489898 (19:44777292 CAA>C,CA,CAAA), RS1001559609 (19:44796169 C>A,T)

Disease associations

OMIM: gene MIM:608453 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5724772 (SINGLE PROTEIN)

Clinical evidence (CIViC)

Drug × variant × indication: 1 predictive associations from 1 curated evidence items.

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

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

Binding affinities (BindingDB)

444 measured of 445 human assays (445 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
(S)-2-(6-(cyclopentyloxy)-4-(3-((4- methyl-4H-1,2,4-triazol-3- yl)methyl)oxetan-3-yl)pyridin-2-yl)-6- ((2-isopropyl-4-methylpiperazin-1- yl)methyl)-4-(trifluoromethyl)isoindolin- 1-one	IC50	5.5 nM	US-20250230147: LACTAMS AS CBL-B INHIBITORS
2-[6-cyclopropyl-4-[3-[(4-methyl-1,2,4-triazol-3-yl)methyl]oxetan-3-yl]-2-pyridinyl]-6-[[(1-methylcyclobutyl)amino]methyl]-4-(trifluoromethyl)-3H-isoindol-1-one	IC50	5.6 nM	US-20250230147: LACTAMS AS CBL-B INHIBITORS
2-[3-[3,3-difluoro-1-[(4-methyl-1,2,4-triazol-3-yl)methyl]cyclobutyl]phenyl]-6-[(1S)-1-[(1-methylcyclobutyl)amino]ethyl]-4-(trifluoromethyl)-3H-isoindol-1-one	IC50	5.8 nM	US-20250230147: LACTAMS AS CBL-B INHIBITORS
2-[3-(ethylamino)-5-[1-[(4-methyl-1,2,4-triazol-3-yl)methyl]cyclobutyl]phenyl]-6-[[(1-methylcyclobutyl)amino]methyl]-4-(trifluoromethyl)-3H-isoindol-1-one	IC50	6 nM	US-20250230147: LACTAMS AS CBL-B INHIBITORS
2-[3-[3,3-difluoro-1-[(4-methyl-1,2,4-triazol-3-yl)methyl]cyclobutyl]-5-(ethylamino)phenyl]-6-[[(1-methylcyclobutyl)amino]methyl]-4-(trifluoromethyl)-3H-isoindol-1-one	IC50	6.4 nM	US-20250230147: LACTAMS AS CBL-B INHIBITORS
2-[3-[3-[(R)-fluoro-(4-methyl-1,2,4-triazol-3-yl)methyl]oxetan-3-yl]phenyl]-6-[(1S)-1-[(1-methylcyclobutyl)amino]ethyl]-4-(trifluoromethyl)-3H-isoindol-1-one	IC50	6.7 nM	US-20250230147: LACTAMS AS CBL-B INHIBITORS
2-(6-(ethylthio)-4-(1-((4-methyl-4H- 1,2,4-triazol-3- yl)methyl)cyclobutyl)pyridin-2-yl)-6-(((1- methylcyclobutyl)amino)methyl)-4- (trifluoromethyl)isoindolin-1-one	IC50	6.8 nM	US-20250230147: LACTAMS AS CBL-B INHIBITORS
2-(3-(3-((R)-fluoro(4-methyl-4H-1,2,4- triazol-3-yl)methyl)oxetan-3-yl)phenyl)- 6-(((S)-2-methyl-1,4-oxazepan-4- yl)methyl)-4-(trifluoromethyl)isoindolin- 1-one	IC50	7 nM	US-20250230147: LACTAMS AS CBL-B INHIBITORS
(S)-2-(6-(allylamino)-4-(1-((4-methyl- 4H-1,2,4-triazol-3- yl)methyl)cyclobutyl)pyridin-2-yl)-6-((2- isopropyl-4-methylpiperazin-1- yl)methyl)-4-(trifluoromethyl)isoindolin- 1-one	IC50	7 nM	US-20250230147: LACTAMS AS CBL-B INHIBITORS
2-[4-[3,3-difluoro-1-[(4-methyl-1,2,4-triazol-3-yl)methyl]cyclobutyl]-6-(ethylamino)-2-pyridinyl]-6-[[(2S)-4-methyl-2-propan-2-ylpiperazin-1-yl]methyl]-4-(trifluoromethyl)-3H-isoindol-1-one	IC50	7.1 nM	US-20250230147: LACTAMS AS CBL-B INHIBITORS
(S)-6-((2-isopropyl-4-methylpiperazin- 1-yl)methyl)-2-(3-(3-((4-methyl-4H- 1,2,4-triazol-3-yl)methyl)oxetan-3- yl)phenyl)-4-(trifluoromethyl)isoindolin- 1-one	IC50	7.1 nM	US-20250230147: LACTAMS AS CBL-B INHIBITORS
2-[4-[1-[(S)-fluoro-(4-methyl-1,2,4-triazol-3-yl)methyl]cyclobutyl]-6-(2-hydroxyethylamino)-2-pyridinyl]-6-[[(2S)-4-methyl-2-propan-2-ylpiperazin-1-yl]methyl]-4-(trifluoromethyl)-3H-isoindol-1-one	IC50	7.2 nM	US-20250230147: LACTAMS AS CBL-B INHIBITORS
(S)-2-(3-(3,3-difluoro-1-((4-methyl-4H- 1,2,4-triazol-3- yl)methyl)cyclobutyl)phenyl)-6-((2- isopropyl-4-methylpiperazin-1- yl)methyl)-4-(trifluoromethyl)isoindolin- 1-one	IC50	7.5 nM	US-20250230147: LACTAMS AS CBL-B INHIBITORS
2-[3-[3-[(R)-fluoro-(4-methyl-1,2,4-triazol-3-yl)methyl]oxetan-3-yl]phenyl]-6-[(1R)-1-[(1-methylcyclobutyl)amino]ethyl]-4-(trifluoromethyl)-3H-isoindol-1-one	IC50	7.6 nM	US-20250230147: LACTAMS AS CBL-B INHIBITORS
2-(6-((cyclopropylmethyl)amino)-4-(1- ((S)-fluoro(4-methyl-4H-1,2,4-triazol-3- yl)methyl)cyclobutyl)pyridin-2-yl)-6- (((S)-2-isopropyl-4-methylpiperazin-1- yl)methyl)-4-(trifluoromethyl)isoindolin- 1-one	IC50	7.9 nM	US-20250230147: LACTAMS AS CBL-B INHIBITORS
2-(3-(3-((R)-fluoro(4-methyl-4H-1,2,4- triazol-3-yl)methyl)oxetan-3-yl)phenyl)- 6-(((S)-4-(2-fluoroethyl)-2- isopropylpiperazin-1-yl)methyl)-4- (trifluoromethyl)isoindolin-1-one	IC50	8 nM	US-20250230147: LACTAMS AS CBL-B INHIBITORS
2-(3-(1-((R)-fluoro(4-methyl-4H-1,2,4- triazol-3-yl)methyl)cyclobutyl)phenyl)-6- (((S)-2-isopropylpiperazin-1-yl)methyl)- 4-(trifluoromethyl)isoindolin-1-one	IC50	8 nM	US-20250230147: LACTAMS AS CBL-B INHIBITORS
2-(6-ethoxy-4-(1-((4-methyl-4H-1,2,4- triazol-3-yl)methyl)cyclobutyl)pyridin-2- yl)-6-(((1- methylcyclobutyl)amino)methyl)-4- (trifluoromethyl)isoindolin-1-one	IC50	8 nM	US-20250230147: LACTAMS AS CBL-B INHIBITORS
(R)-4-bromo-2-(3-(3-(fluoro(4-methyl- 4H-1,2,4-triazol-3-yl)methyl)oxetan-3- yl)phenyl)-6-(((1- methylcyclobutyl)amino)methyl) isoindolin-1-one	IC50	8.2 nM	US-20250230147: LACTAMS AS CBL-B INHIBITORS
2-[4-[1-[(R)-fluoro-(4-methyl-1,2,4-triazol-3-yl)methyl]cyclobutyl]-6-(2-hydroxyethylamino)-2-pyridinyl]-6-[[(2S)-4-methyl-2-propan-2-ylpiperazin-1-yl]methyl]-4-(trifluoromethyl)-3H-isoindol-1-one	IC50	8.3 nM	US-20250230147: LACTAMS AS CBL-B INHIBITORS
2-(3-(isopropylamino)-5-(1-((4-methyl- 4H-1,2,4-triazol-3- yl)methyl)cyclobutyl)phenyl)-6-(((1- methylcyclobutyl)amino)methyl)-4- (trifluoromethyl)isoindolin-1-one	IC50	8.3 nM	US-20250230147: LACTAMS AS CBL-B INHIBITORS
(S)-2-(6-(cyclopentylamino)-4-(3-((4- methyl-4H-1,2,4-triazol-3- yl)methyl)oxetan-3-yl)pyridin-2-yl)-6- ((2-isopropyl-4-methylpiperazin-1- yl)methyl)-4-(trifluoromethyl)isoindolin- 1-one formate	IC50	9.1 nM	US-20250230147: LACTAMS AS CBL-B INHIBITORS
2-(6-(cyclopentyloxy)-4-(3-((4-methyl- 4H-1,2,4-triazol-3-yl)methyl)oxetan-3- yl)pyridin-2-yl)-6-(((1- methylcyclobutyl)amino)methyl)-4- (trifluoromethyl)isoindolin-1-one	IC50	9.5 nM	US-20250230147: LACTAMS AS CBL-B INHIBITORS
6-((S)-1-amino-2-cyclopropylethyl)-2- (3-(3-((R)-fluoro(4-methyl-4H-1,2,4- triazol-3-yl)methyl)oxetan-3-yl)phenyl)- 4-(trifluoromethyl)isoindolin-1-one	IC50	9.6 nM	US-20250230147: LACTAMS AS CBL-B INHIBITORS
(R)-2-(3-(3-(fluoro(4-methyl-4H-1,2,4- triazol-3-yl)methyl)oxetan-3-yl)phenyl)- 6-(((3-fluoropropyl)amino)methyl)-4- (trifluoromethyl)isoindolin-1-one	IC50	9.8 nM	US-20250230147: LACTAMS AS CBL-B INHIBITORS
2-(6-(cyclopentylamino)-4-(3-((4- methyl-4H-1,2,4-triazol-3- yl)methyl)oxetan-3-yl)pyridin-2-yl)-6- (((1-methylcyclobutyl)amino)methyl)-4- (trifluoromethyl)isoindolin-1-one	IC50	9.9 nM	US-20250230147: LACTAMS AS CBL-B INHIBITORS
2-(3-(3,3-difluoro-1-((S)-fluoro(4- methyl-4H-1,2,4-triazol-3- yl)methyl)cyclobutyl)phenyl)-6-(((S)-4- ethyl-2-isopropylpiperazin-1-yl)methyl)- 4-(trifluoromethyl)isoindolin-1-one	IC50	9.9 nM	US-20250230147: LACTAMS AS CBL-B INHIBITORS
2-(6-(ethylamino)-4-(3-((4-methyl-4H- 1,2,4-triazol-3-yl)methyl)oxetan-3- yl)pyridin-2-yl)-6-(((1- methylcyclobutyl)amino)methyl)-4- (trifluoromethyl)isoindolin-1-one	IC50	10 nM	US-20250230147: LACTAMS AS CBL-B INHIBITORS
2-(4-(1-((4-methyl-4H-1,2,4-triazol-3- yl)methyl)cyclobutyl)-6- (methylamino)pyridin-2-yl)-6-(((1- methylcyclobutyl)amino)methyl)-4- (trifluoromethyl)isoindolin-1-one formate	IC50	10 nM	US-20250230147: LACTAMS AS CBL-B INHIBITORS
(S)-2-(6-ethoxy-4-(1-((4-methyl-4H- 1,2,4-triazol-3- yl)methyl)cyclobutyl)pyridin-2-yl)-6-((2- isopropyl-4-methylpiperazin-1 - yl)methyl)-4-(trifluoromethyl)isoindolin- 1-one	IC50	10 nM	US-20250230147: LACTAMS AS CBL-B INHIBITORS
2-(3-(3-((R)-fluoro(4-methyl-4H-1,2,4- triazol-3-yl)methyl)oxetan-3-yl)phenyl)- 6-(((S)-2-isopropyl-4-methylpiperazin- 1-yl)methyl)-4- (trifluoromethyl)isoindolin-1-one	IC50	11 nM	US-20250230147: LACTAMS AS CBL-B INHIBITORS
2-[3-[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	IC50	11 nM	US-20250230147: LACTAMS AS CBL-B INHIBITORS
2-[6-(cyclopropylmethylamino)-4-[1-[(4-methyl-1,2,4-triazol-3-yl)methyl]cyclobutyl]-2-pyridinyl]-6-[[(1-methylcyclobutyl)amino]methyl]-4-(trifluoromethyl)-3H-isoindol-1-one	IC50	11 nM	US-20250230147: LACTAMS AS CBL-B INHIBITORS
6-[[(1-methylcyclobutyl)amino]methyl]-2-[6-methylsulfanyl-4-[1-[(4-methyl-1,2,4-triazol-3-yl)methyl]cyclobutyl]-2-pyridinyl]-4-(trifluoromethyl)-3H-isoindol-1-one	IC50	11 nM	US-20250230147: LACTAMS AS CBL-B INHIBITORS
(S)-6-(6-((2-isopropyl-4- methylpiperazin-1-yl)methyl)-1-oxo-4- (trifluoromethyl)isoindolin-2-yl)-4-(1-((4- methyl-4H-1,2,4-triazol-3- yl)methyl)cyclobutyl)picolinonitrile	IC50	11 nM	US-20250230147: LACTAMS AS CBL-B INHIBITORS
2-(6-ethoxy-4-(3-((4-methyl-4H-1,2,4- triazol-3-yl)methyl)oxetan-3-yl)pyridin- 2-yl)-6-(((1- methylcyclobutyl)amino)methyl)-4- (trifluoromethyl)isoindolin-1-one	IC50	11 nM	US-20250230147: LACTAMS AS CBL-B INHIBITORS
2-(4-(1-((4-methyl-4H-1,2,4-triazol-3- yl)methyl)cyclobutyl)-6- (methylthio)pyridin-2-yl)-6-(((1- methylcyclobutyl)amino)methyl)-4- (trifluoromethyl)isoindolin-1-one	IC50	11 nM	US-20250230147: LACTAMS AS CBL-B INHIBITORS
6-(((cyclopropylmethyl)amino)methyl)- 2-(3-(3,3-difluoro-1-((4-methyl-4H- 1,2,4-triazol-3- yl)methyl)cyclobutyl)phenyl)-4- (trifluoromethyl)isoindolin-1-one	IC50	11 nM	US-20250230147: LACTAMS AS CBL-B INHIBITORS
2-(6-isobutyl-4-(1-((4-methyl-4H-1,2,4- triazol-3-yl)methyl)cyclobutyl)pyridin-2- yl)-6-(((1- methylcyclobutyl)amino)methyl)-4- (trifluoromethyl)isoindolin-1-one formate	IC50	11 nM	US-20250230147: LACTAMS AS CBL-B INHIBITORS
2-(6-butyl-4-(1-((4-methyl-4H-1,2,4- triazol-3-yl)methyl)cyclobutyl)pyridin-2- yl)-6-(((1- methylcyclobutyl)amino)methyl)-4- (trifluoromethyl)isoindolin-1-one	IC50	11 nM	US-20250230147: LACTAMS AS CBL-B INHIBITORS
2-(6-ethoxy-4-(1-((4-methyl-4H-1,2,4- triazol-3-yl)methyl)cyclobutyl)pyridin-2- yl)-6-(((1- methylcyclobutyl)amino)methyl)-4- (trifluoromethyl)isoindolin-1-one	IC50	11 nM	US-20250230147: LACTAMS AS CBL-B INHIBITORS
2-(6-((cyclopropylmethyl)amino)-4-(1- ((4-methyl-4H-1,2,4-triazol-3- yl)methyl)cyclobutyl)pyridin-2-yl)-6-(((1- methylcyclobutyl)amino)methyl)-4- (trifluoromethyl)isoindolin-1-one	IC50	11 nM	US-20250230147: LACTAMS AS CBL-B INHIBITORS
2-(3-(ethylamino)-5-(3-((4-methyl-4H- 1,2,4-triazol-3-yl)methyl)oxetan-3- yl)phenyl)-6-(((1- methylcyclobutyl)amino)methyl)-4- (trifluoromethyl)isoindolin-1-one	IC50	11 nM	US-20250230147: LACTAMS AS CBL-B INHIBITORS
2-(3-(3((R)-fluoro(4-methyl-4H-1,2,4- triazol-3-yl)methyl)oxetan-3-yl)phenyl)- 6-(((S)-2-isopropylpiperazin-1- yl)methyl)-4-(trifluoromethyl)isoindolin- 1-one	IC50	12 nM	US-20250230147: LACTAMS AS CBL-B INHIBITORS
2-(3-(3,3-difluoro-1-((R)-fluoro(4- methyl-4H-1,2,4-triazol-3- yl)methyl)cyclobutyl)phenyl)-6-(((S)-2- isopropyl-4-methylpiperazin-1- yl)methyl)-4-(trifluoromethyl)isoindolin- 1-one	IC50	12 nM	US-20250230147: LACTAMS AS CBL-B INHIBITORS
(R)-2-(3-(3-(fluoro(4-methyl-4H-1,2,4- triazol-3-yl)methyl)oxetan-3-yl)phenyl)- 6-((propylamino)methyl)-4- (trifluoromethyl)isoindolin-1-one formate	IC50	12 nM	US-20250230147: LACTAMS AS CBL-B INHIBITORS
(R)-2-(3-(3-(fluoro(4-methyl-4H-1,2,4- triazol-3-yl)methyl)oxetan-3-yl)phenyl)- 6-(((1- methylcyclopropyl)amino)methyl)-4- (trifluoromethyl)isoindolin-1-one	IC50	12 nM	US-20250230147: LACTAMS AS CBL-B INHIBITORS
4-(2,2-difluoroethyl)-2-[3-[3-[(R)-fluoro-(4-methyl-1,2,4-triazol-3-yl)methyl]oxetan-3-yl]phenyl]-6-[[(1-methylcyclobutyl)amino]methyl]-3H-isoindol-1-one	IC50	12 nM	US-20250230147: LACTAMS AS CBL-B INHIBITORS
4-(2,2-difluoroethyl)-2-[3-[3,3-difluoro-1-[(4-methyl-1,2,4-triazol-3-yl)methyl]cyclobutyl]phenyl]-6-[[(1-methylcyclobutyl)amino]methyl]-3H-isoindol-1-one	IC50	12 nM	US-20250230147: LACTAMS AS CBL-B INHIBITORS

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	decreases expression, decreases methylation, increases expression	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	increases expression, affects cotreatment	1
ICG 001	decreases expression	1
dorsomorphin	affects cotreatment, increases expression	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)

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