CBLB

Summary

CBLB (Cbl proto-oncogene B, HGNC:1542) is a protein-coding gene on chromosome 3q13.11, encoding E3 ubiquitin-protein ligase CBL-B (Q13191). E3 ubiquitin-protein ligase which accepts ubiquitin from specific E2 ubiquitin-conjugating enzymes, and transfers it to substrates, generally promoting their degradation by the proteasome.

This gene encodes an E3 ubiquitin-protein ligase which promotes proteosome-mediated protein degradation by transferring ubiquitin from an E2 ubiquitin-conjugating enzyme to a substrate. The encoded protein is involved in the regulation of immune response by limiting T-cell receptor, B-cell receptor, and high affinity immunoglobulin epsilon receptor activation. Studies in mouse suggest that this gene is involved in antifungal host defense and that its inhibition leads to increased fungal killing. Manipulation of this gene may be beneficial in implementing immunotherapies for a variety of conditions, including cancer, autoimmune diseases, allergies, and infections.

Source: NCBI Gene 868 — RefSeq curated summary.

At a glance

• Gene–disease (curated): autoimmune disease, multisystem, infantile-onset, 3 (Strong, GenCC)
• Clinical variants (ClinVar): 164 total — 3 pathogenic, 1 likely-pathogenic
• Phenotypes (HPO): 22
• Druggable target: yes
• Cancer driver (intOGen): activating (oncogene-like) across 2 cancer types
• MANE Select transcript: NM_170662

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:1542
Approved symbol	CBLB
Name	Cbl proto-oncogene B
Location	3q13.11
Locus type	gene with protein product
Status	Approved
Aliases	RNF56, Cbl-b
Ensembl gene	ENSG00000114423
Ensembl biotype	protein_coding
OMIM	604491
Entrez	868

Gene structure

Transcript identifiers

Ensembl transcripts: 31 — 22 protein_coding, 6 nonsense_mediated_decay, 2 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000394030, ENST00000403724, ENST00000405772, ENST00000407712, ENST00000438603, ENST00000443752, ENST00000447441, ENST00000476370, ENST00000642241, ENST00000642907, ENST00000643192, ENST00000643322, ENST00000643403, ENST00000645425, ENST00000645759, ENST00000646499, ENST00000646825, ENST00000856778, ENST00000856779, ENST00000856780, ENST00000856781, ENST00000856782, ENST00000856783, ENST00000856784, ENST00000856785, ENST00000856786, ENST00000931151, ENST00000954007, ENST00000954008, ENST00000954009, ENST00000954010

RefSeq mRNA: 21 — MANE Select: NM_170662 NM_001321786, NM_001321788, NM_001321789, NM_001321790, NM_001321791, NM_001321793, NM_001321794, NM_001321795, NM_001321796, NM_001321797, NM_001321798, NM_001321799, NM_001321806, NM_001321807, NM_001321808, NM_001321811, NM_001321813, NM_001321816, NM_001321820, NM_001321822, NM_170662

CCDS: CCDS2948

Canonical transcript exons

ENST00000394030 — 19 exons

Exon	Start	End
ENSE00000774841	105670233	105670352
ENSE00000774842	105678431	105678571
ENSE00000774843	105681479	105681610
ENSE00000774844	105681724	105681818
ENSE00000774845	105685320	105685466
ENSE00000774846	105693494	105693588
ENSE00001607504	105702094	105702459
ENSE00001628201	105751462	105751618
ENSE00001654827	105720047	105720250
ENSE00001686511	105776396	105776542
ENSE00001755904	105655461	105659229
ENSE00001767402	105703988	105704173
ENSE00003579917	105745917	105746038
ENSE00003607906	105737171	105737258
ENSE00003646928	105740494	105740631
ENSE00003680223	105867410	105867591
ENSE00003684823	105734009	105734140
ENSE00003786932	105853414	105853664
ENSE00003840564	105868736	105869012

Expression profiles

Bgee: expression breadth ubiquitous, 274 present calls, max score 97.22.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 27.3267 / max 371.7705, expressed in 1811 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
43600	22.6523	1803
43593	1.6728	564
43598	0.9513	539
43601	0.7496	391
43597	0.6716	358
43603	0.3732	167
43599	0.2558	128

Top tissues by expression

291 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
pericardium	UBERON:0002407	97.22	gold quality
colonic epithelium	UBERON:0000397	93.93	gold quality
calcaneal tendon	UBERON:0003701	93.41	gold quality
cauda epididymis	UBERON:0004360	93.19	gold quality
saphenous vein	UBERON:0007318	93.07	gold quality
cortical plate	UBERON:0005343	92.54	gold quality
mucosa of stomach	UBERON:0001199	92.49	gold quality
tibia	UBERON:0000979	92.30	gold quality
decidua	UBERON:0002450	91.99	gold quality
adrenal tissue	UBERON:0018303	91.72	gold quality
tibial nerve	UBERON:0001323	91.70	gold quality
visceral pleura	UBERON:0002401	91.57	gold quality
subcutaneous adipose tissue	UBERON:0002190	91.56	gold quality
omental fat pad	UBERON:0010414	91.34	gold quality
peritoneum	UBERON:0002358	91.33	gold quality
stromal cell of endometrium	CL:0002255	91.00	gold quality
apex of heart	UBERON:0002098	90.95	gold quality
adipose tissue of abdominal region	UBERON:0007808	90.82	gold quality
jejunal mucosa	UBERON:0000399	90.58	gold quality
heart left ventricle	UBERON:0002084	90.55	gold quality
cardiac ventricle	UBERON:0002082	90.49	gold quality
right atrium auricular region	UBERON:0006631	90.23	gold quality
ganglionic eminence	UBERON:0004023	90.22	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	89.83	gold quality
sural nerve	UBERON:0015488	89.82	gold quality
pleura	UBERON:0000977	89.51	gold quality
heart	UBERON:0000948	89.44	gold quality
sperm	CL:0000019	89.38	gold quality
lymph node	UBERON:0000029	89.29	gold quality
parietal pleura	UBERON:0002400	89.27	gold quality

Single-cell (SCXA)

Detected in 8 experiment(s), a significant marker in 5.

Experiment	Marker?	Max mean expression
E-CURD-119	yes	42.33
E-CURD-122	yes	41.06
E-CURD-88	yes	17.91
E-CURD-112	yes	16.80
E-MTAB-11268	no	1453.75
E-ANND-2	no	1422.90
E-GEOD-124858	no	1175.71
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): FOXO3

miRNA regulators (miRDB)

225 targeting CBLB, 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-3163	100.00	77.23	8605
HSA-MIR-3064-3P	100.00	70.09	1254
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-4776-3P	100.00	68.73	1340
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-6740-5P	100.00	65.64	932
HSA-MIR-518D-5P	100.00	67.51	979
HSA-MIR-518E-5P	100.00	67.66	954
HSA-MIR-518F-5P	100.00	67.51	979
HSA-MIR-519A-5P	100.00	67.66	954
HSA-MIR-519B-5P	100.00	67.66	954
HSA-MIR-519C-5P	100.00	67.66	954
HSA-MIR-520C-5P	100.00	67.51	979
HSA-MIR-522-5P	100.00	67.66	954
HSA-MIR-523-5P	100.00	67.66	954
HSA-MIR-526A-5P	100.00	67.51	979
HSA-MIR-4455	100.00	65.48	1587
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-223-3P	99.99	70.14	1140

Literature-anchored findings (GeneRIF, showing 40)

• novel E3 ubiquitin-protein ligase; role in regulation of immune response - review (PMID:11826757)
• Cbl-b plays a negative role in Crk-L-C3G-mediated Rap1 and LFA-1 activation in T cells. (PMID:12697763)
• Expression of Cbl-b effectively blocks the ability of Cool-2 to stimulate PAK, providing an additional mechanism, aside from catalyzing receptor ubiquitination, by which Cbl-b acts as a negative regulator for signaling activities requiring PAK activation. (PMID:12935897)
• Cbl-b is a negative regulator of both Lyn-Syk-LAT and Gab2mediated complementary signaling pathways in FcepsilonRI-mediated mast cell activation (PMID:14604964)
• Differences in ubiquitin-binding may reflect distinct regulatory functions of c-Cbl and Cbl-b. (PMID:15273720)
• genetic interaction between the CTLA4 and CBLB genes in type 1 diabetes (PMID:15629882)
• NF-kappaB activity is enhanced by a PI3K signal mediated by Cbl-b and Rho (PMID:15922296)
• results suggest that Cbl-b- or atrogin-1-mediated ubiquitination plays an important role in unloading-induced muscle atrophy, and that unloading stress may preferentially inhibit transcriptional responses in skeletal muscle (PMID:16868939)
• In a primary analysis, no evidence for an association of the CBLB SNP rs3772534 with disease was found in either sample set in type 1 diabetes. (PMID:17209142)
• the host ubiquitin ligase Cbl-b interacts with the type III-secreted effector exotoxin T (ExoT) and plays a key role in vivo in limiting bacterial dissemination mediated by ExoT (PMID:17235393)
• novel mutations in c-CBL and CBL-b have been identified in human acute myeloid leukemia (PMID:17475912)
• F328L mutation is involved in the development of autoimmune diseases including type 1 diabetes, and also provide insight into the structure-function relationship of CBLB protein (PMID:18201552)
• two Cbls accounted for total receptor ubiquitination and that while c-Cbl and Cbl-b are each alone sufficient to effect EGFR degradation, both are involved in the physiological, EGF-mediated process of receptor downregulation. (PMID:18316398)
• Cbls suppress cell death in healthy neurons at least in part by inhibiting the ability of mixed lineage kinases to activate JNK signaling. (PMID:19546888)
• Overexpressions of c-Cbl, Cbl-b, and EGFR are closely related to the invasion and progression of gastric carcinoma. (PMID:20038312)
• Cbl-b and itch are key regulators of peripheral T-cell tolerance [review] (PMID:20395198)
• Cbl-b plays a positive modulatory role in GPVI-dependent platelet signaling, which translates to an important regulatory role in hemostasis and thrombosis in vivo (PMID:20400514)
• These data provide further evidence of the association of MS disease with variation within CBLB. (PMID:21037273)
• Interplay between transgenic Cblb-dependent T cell anergy and other mechanisms prevents organ-specific islet-cell autoimmunity. (PMID:21248249)
• CBLB mutation is asssociated with chronic myelogenous leukemia. (PMID:21346257)
• Deregulations of Lck-ZAP-70-Cbl-b cross-talk and miR181a in T cells were found to be associated with cholesterol-dependent-dismantling of HLA-DR rafts in macrophages in leprosy progression. (PMID:21453975)
• data suggest that Cbl-b may contribute to the deregulated activation of T lymphocytes observed in systemic lupus erythematosus (SLE); a significant association between the 2126(A/G) SNP and SLE was detected (PMID:21558139)
• the expression and clinical relevance of c-Cbl, Cbl-b and EGFR in non-small cell lung cancer (PMID:21645455)
• c-Cbl as well as Cbl-b may play important roles in Hsp90 inhibitor-induced degradation of Flt3-ITD through the ubiquitin proteasome system (PMID:21768087)
• Over expression of TGF-beta and CTLA-4 leads to T cell hyporesponsiveness, a major hallmark of leprosy, by increasing the expression of Cbl-b. (PMID:21807564)
• Autoinhibition and phosphorylation-induced activation mechanisms of human cancer and autoimmune disease-related E3 protein Cbl-b (PMID:22158902)
• Pooled analysis corroborated the effect on multiple sclerosis predisposition of three genes: TMEM39A, IL12B, and CBLB (PMID:22194214)
• Data show that bufalin-induced down-regulation of Cbl-b contributed to the up-regulation of TRAIL Receptors DR4 and DR5. (PMID:22447040)
• FOXP3 mRNA expression correlated with CBLB and ITCH in MS patients. (PMID:23039885)
• abnormal peripheral tolerance in SLE is caused by a deficiency in Cbl-b, and that this ubiquitin ligase plays a key role in regulating T-cell receptor signaling during the induction of peripheral tolerance. (PMID:23280105)
• that icotinib-induced upregulation of Cbl-b is responsible, at least in part, for the antitumor effect of icotinib via the inhibition of phosphoinositide 3-kinase (PI3K)/Akt and mitogen-activated protein kinase pathways in EGFR-mutated NSCLC cells. (PMID:23586056)
• By up-regulating the expression of c-Cbl and Cbl-b, which leads to inhibition of PI3K/Akt signaling and down-regulation of P-gp expression, beta-elemene is capable of enhancing the efficacy of doxorubicin in leukemia and gastric cancer cells. (PMID:23665906)
• Cbl-b knockdown caused significant increase of phosphorylation of EGFR, ERK and Akt, decrease of mitochondrial membrane potential, and increase of expression ratio of Bcl-2/Bax. (PMID:24351824)
• Ubiquitin ligase Cbl-b represses IGF-I-induced epithelial mesenchymal transition via ZEB2 and microRNA-200c regulation in gastric cancer cells. (PMID:24885194)
• The data suggest a role of the CBLB rs12487066 variant in the interactions of a genetic risk factor and IFN function during viral infections in multiple sclerosis. (PMID:25261476)
• Low CBLB expression is associated with glioma cell invasion. (PMID:25691332)
• Our results suggest that celecoxib-mediated upregulation of Cbl-b is responsible, at least in part, for the additive antitumor effect of celecoxib and rapamycin via inhibition of rapamycin-induced Akt activation. (PMID:25701378)
• Translocation of Cbl-b from the nucleus to the cytoplasm prevented the localization of P-gp to caveolae resulting in the reversal of multidrug resistance through the ubiquitination and degradation of c-Src. (PMID:25788263)
• findings suggest that Cbl-b limits NGF-TrkA signaling to control the length of neurites. (PMID:25921289)
• Results suggest that Cbl-b improves the prognosis of RANK-expressing breast cancer patients by inhibiting RANKL-induced breast cancer cell migration and metastasis. (PMID:26087197)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	cblb	ENSDARG00000015199
mus_musculus	Cblb	ENSMUSG00000022637
rattus_norvegicus	Cblb	ENSRNOG00000001982

Paralogs (2): CBL (ENSG00000110395), CBLC (ENSG00000142273)

Protein

Protein identifiers

E3 ubiquitin-protein ligase CBL-B — Q13191 (reviewed: Q13191)

Alternative names: Casitas B-lineage lymphoma proto-oncogene b, RING finger protein 56, RING-type E3 ubiquitin transferase CBL-B, SH3-binding protein CBL-B, Signal transduction protein CBL-B

All UniProt accessions (11): Q13191, A0A2R8Y582, A0A2R8Y5E1, A0A2R8Y7I2, A0A2R8Y875, A0A2R8Y8D8, A0A2R8YDW4, A0A2R8YFD4, C9JRB3, C9JU85, C9K048

UniProt curated annotations — full annotation on UniProt →

Function. E3 ubiquitin-protein ligase which accepts ubiquitin from specific E2 ubiquitin-conjugating enzymes, and transfers it to substrates, generally promoting their degradation by the proteasome. Negatively regulates TCR (T-cell receptor), BCR (B-cell receptor) and FCER1 (high affinity immunoglobulin epsilon receptor) signal transduction pathways. In naive T-cells, inhibits VAV1 activation upon TCR engagement and imposes a requirement for CD28 costimulation for proliferation and IL-2 production. Also acts by promoting PIK3R1/p85 ubiquitination, which impairs its recruitment to the TCR and subsequent activation. In activated T-cells, inhibits PLCG1 activation and calcium mobilization upon restimulation and promotes anergy. Involved in LAG3-mediated inhibition of TCR signaling: following ligand-binding to LAG3, catalyzes ‘Lys-63’-linked ubiquitination of LAG3, unleashing the LAG3 C-terminus from the membrane, and initiating a signaling that prevents TCR activation. In B-cells, acts by ubiquitinating SYK and promoting its proteasomal degradation. Slightly promotes SRC ubiquitination. May be involved in EGFR ubiquitination and internalization. May be functionally coupled with the E2 ubiquitin-protein ligase UB2D3. In association with CBL, required for proper feedback inhibition of ciliary platelet-derived growth factor receptor-alpha (PDGFRA) signaling pathway via ubiquitination and internalization of PDGFRA.

Subunit / interactions. Interacts with SH3 domain-containing proteins LCK, CRK and SORBS1. Interacts with LCP2 and ZAP70. Interacts with CBL. Interacts with SH3 domain-containing proteins VAV1, FYN, FGR, PLCG1, GRB2, CRKL, PIK3R1 and SH3KBP1/CIN85. Identified in heterotrimeric complexes with SH3KBP1/CIN85, CD2AP and ARHGEF7, where one CBLB peptide binds two copies of the other protein. Interacts with poly-ubiquitinated proteins. Dimerization is required for the binding of poly-ubiquitin, but not for the binding of mono-ubiquitin. Interacts with EGFR (phosphorylated). Interacts with IFT20.

Subcellular location. Cytoplasm.

Tissue specificity. Expressed in placenta, heart, lung, kidney, spleen, ovary and testis, as well as fetal brain and liver and hematopoietic cell lines, but not in adult brain, liver, pancreas, salivary gland, or skeletal muscle. Present in lymphocytes (at protein level).

Post-translational modifications. Phosphorylated on tyrosine and serine residues upon TCR or BCR activation, and upon various types of cell stimulation. Auto-ubiquitinated upon EGF-mediated cell activation or upon T-cell costimulation by CD28; which promotes proteasomal degradation.

Disease relevance. Autoimmune disease, multisystem, infantile-onset, 3 (ADMIO3) [MIM:620430] An autosomal recessive disorder characterized by autoimmune manifestations apparent in the first months or years of life. Clinical features may include hypothyroidism, type 1 diabetes mellitus, systemic inflammatory manifestations such as fever and hepatomegaly, and autoimmune cytopenias. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. 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. The UBA domain interacts with poly-ubiquitinated proteins.

Induction. By serum starvation.

Pathway. Protein modification; protein ubiquitination.

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

Isoforms (3)

UniProt ID	Names	Canonical?
Q13191-1	Long	yes
Q13191-2	Truncated 1
Q13191-3	Truncated 2

RefSeq proteins (21): NP_001308715, NP_001308717, NP_001308718, NP_001308719, NP_001308720, NP_001308722, NP_001308723, NP_001308724, NP_001308725, NP_001308726, NP_001308727, NP_001308728, NP_001308735, NP_001308736, NP_001308737, NP_001308740, NP_001308742, NP_001308745, NP_001308749, NP_001308751, NP_733762* (*=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
IPR015940	UBA	Domain
IPR017907	Znf_RING_CS	Conserved_site
IPR018957	Znf_C3HC4_RING-type	Domain
IPR024159	Cbl_PTB	Domain
IPR024162	Adaptor_Cbl	Family
IPR036537	Adaptor_Cbl_N_dom_sf	Homologous_superfamily
IPR036860	SH2_dom_sf	Homologous_superfamily
IPR039520	CBL-B_RING-HC	Domain

Pfam: PF00097, PF02262, PF02761, PF02762

UniProt features (108 total): helix 24, strand 16, mutagenesis site 14, modified residue 12, region of interest 9, compositionally biased region 7, turn 6, binding site 6, sequence variant 5, splice variant 3, domain 2, sequence conflict 2, chain 1, zinc finger region 1

Structure

Experimental structures (PDB)

24 structures.

PDB	Method	Resolution (Å)
8QTG	X-RAY DIFFRACTION	1.42
8QTJ	X-RAY DIFFRACTION	1.52
2OOA	X-RAY DIFFRACTION	1.56
9FQJ	X-RAY DIFFRACTION	1.56
2J6F	X-RAY DIFFRACTION	1.7
8VW5	X-RAY DIFFRACTION	1.76
9FQH	X-RAY DIFFRACTION	1.79
8GCY	X-RAY DIFFRACTION	1.81
2AK5	X-RAY DIFFRACTION	1.85
8QTK	X-RAY DIFFRACTION	1.87
2OOB	X-RAY DIFFRACTION	1.9
9FQI	X-RAY DIFFRACTION	1.95
2BZ8	X-RAY DIFFRACTION	2
8QNH	X-RAY DIFFRACTION	2
8QNG	X-RAY DIFFRACTION	2.2
8QTH	X-RAY DIFFRACTION	2.2
3ZNI	X-RAY DIFFRACTION	2.21
3PFV	X-RAY DIFFRACTION	2.27
8VW4	X-RAY DIFFRACTION	2.4
8QNI	X-RAY DIFFRACTION	2.48
3VGO	X-RAY DIFFRACTION	3.1
2DO6	SOLUTION NMR
2JNH	SOLUTION NMR
2LDR	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q13191-F1	62.88	0.30

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 (6): 221; 223; 225; 227; 232; 286

Post-translational modifications (12): 282, 363, 476, 480, 484, 521, 525, 529, 634, 665, 709, 889

Mutagenesis-validated functional residues (14):

Position	Phenotype
298	inhibits interaction with syk. no effect on e3 activity.
363	decreases affinity for e2 ubiquitin-conjugating enzymes.
373	abolishes e3 activity but does not affect binding to substrates.
665	slightly inhibits interaction with crkl. abolishes interaction with crkl; when associated with f-709.
709	inhibits interaction with crkl. abolishes interaction with crkl; when associated with f-665.
904	no effect on interaction with cd2ap. reduced interaction with sh3kbp1. strongly reduced interaction with sh3kbp1; when a
907	no effect on interaction with sh3kbp1. reduced interaction with cd2ap. strongly reduced interaction with cd2ap; when ass
911	reduced interaction with cd2ap and with sh3kbp1. strongly reduced interaction with cd2ap; when associated with a-907. st
937	loss of ubiquitin binding. reduced levels of tyrosine phosphorylation.
940	loss of ubiquitin binding. reduced levels of tyrosine phosphorylation.
943–944	abolishes interaction with ubiquitinated proteins.
946	loss of ubiquitin binding. reduced levels of tyrosine phosphorylation.
966	interferes with dimerization. reduced e3 ubiquitin-protein ligase activity. reduced levels of tyrosine phosphorylation.
967	no effect on interaction with ubiquitinated proteins.

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-983168	Antigen processing: Ubiquitination & Proteasome degradation
R-HSA-1280218	Adaptive Immune System
R-HSA-168256	Immune System
R-HSA-983169	Class I MHC mediated antigen processing & presentation

MSigDB gene sets: 486 (showing top): GOBP_PLATELET_DERIVED_GROWTH_FACTOR_RECEPTOR_SIGNALING_PATHWAY, GOBP_REGULATION_OF_T_CELL_RECEPTOR_SIGNALING_PATHWAY, GOBP_REGULATION_OF_CELL_ACTIVATION, RNGTGGGC_UNKNOWN, GOBP_REGULATION_OF_ANTIGEN_RECEPTOR_MEDIATED_SIGNALING_PATHWAY, GOBP_REGULATION_OF_LEUKOCYTE_PROLIFERATION, KOBAYASHI_EGFR_SIGNALING_24HR_UP, BROWNE_HCMV_INFECTION_6HR_DN, GOBP_REGULATION_OF_ALPHA_BETA_T_CELL_ACTIVATION, GOBP_REGULATION_OF_ERBB_SIGNALING_PATHWAY, GOBP_TOLERANCE_INDUCTION, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, GOBP_INTRACELLULAR_PROTEIN_TRANSPORT, REACTOME_CLASS_I_MHC_MEDIATED_ANTIGEN_PROCESSING_PRESENTATION, REACTOME_ANTIGEN_PROCESSING_UBIQUITINATION_PROTEASOME_DEGRADATION

GO Biological Process (25): positive regulation of T cell anergy (GO:0002669), T cell anergy (GO:0002870), NLS-bearing protein import into nucleus (GO:0006607), immune response (GO:0006955), signal transduction (GO:0007165), protein catabolic process (GO:0030163), positive regulation of protein ubiquitination (GO:0031398), intracellular signal transduction (GO:0035556), CD4-positive, alpha-beta T cell proliferation (GO:0035739), negative regulation of epidermal growth factor receptor signaling pathway (GO:0042059), positive regulation of protein catabolic process (GO:0045732), protein stabilization (GO:0050821), T cell receptor signaling pathway (GO:0050852), negative regulation of T cell receptor signaling pathway (GO:0050860), negative regulation of T cell activation (GO:0050868), protein K63-linked ubiquitination (GO:0070534), regulation of postsynaptic neurotransmitter receptor internalization (GO:0099149), regulation protein catabolic process at postsynapse (GO:0140252), negative regulation of CD4-positive, alpha-beta T cell proliferation (GO:2000562), regulation of platelet-derived growth factor receptor-alpha signaling pathway (GO:2000583), cell surface receptor signaling pathway (GO:0007166), protein ubiquitination (GO:0016567), regulation of signaling (GO:0023051), regulation of cell adhesion (GO:0030155), T cell activation (GO:0042110)

GO Molecular Function (9): phosphotyrosine residue binding (GO:0001784), calcium ion binding (GO:0005509), zinc ion binding (GO:0008270), 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 (7): nucleoplasm (GO:0005654), cytosol (GO:0005829), plasma membrane (GO:0005886), membrane raft (GO:0045121), postsynapse (GO:0098794), glutamatergic synapse (GO:0098978), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Class I MHC mediated antigen processing & presentation	1
Immune System	1
Adaptive Immune System	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
intracellular anatomical structure	2
synapse	2
positive regulation of T cell tolerance induction	1
regulation of T cell anergy	1
T cell anergy	1
positive regulation of lymphocyte anergy	1
lymphocyte anergy	1
T cell tolerance induction	1
protein import into nucleus	1
immune system process	1
response to stimulus	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
macromolecule catabolic process	1
protein metabolic process	1
protein ubiquitination	1
regulation of protein ubiquitination	1
positive regulation of protein modification by small protein conjugation or removal	1
signal transduction	1
CD4-positive, alpha-beta T cell activation	1
alpha-beta T cell proliferation	1
epidermal growth factor receptor signaling pathway	1
regulation of epidermal growth factor receptor signaling pathway	1
negative regulation of ERBB signaling pathway	1
positive regulation of catabolic process	1
protein catabolic process	1
regulation of protein catabolic process	1
positive regulation of protein metabolic process	1
regulation of protein stability	1
antigen receptor-mediated signaling pathway	1
T cell receptor signaling pathway	1
regulation of T cell receptor signaling pathway	1
negative regulation of antigen receptor-mediated signaling pathway	1
T cell activation	1
regulation of T cell activation	1
negative regulation of lymphocyte activation	1

Protein interactions and networks

STRING

729 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CBLB	CAPN5	O15484	633
CBLB	CD81	P18582	622
CBLB	SH3KBP1	Q96B97	529
CBLB	UBE2U	Q5VVX9	508
CBLB	FGF11	Q92914	385
CBLB	GRB2	P29354	384
CBLB	UBE3C	Q15386	370
CBLB	CXCL14	O95715	368
CBLB	PCNP	Q8WW12	353
CBLB	TULP4	Q9NRJ4	353
CBLB	MYCBP2	O75592	353
CBLB	SESN2	P58004	351
CBLB	MLLT3	P42568	351
CBLB	KLHL2	O95198	350
CBLB	HECW2	Q9P2P5	349
CBLB	DYRK1B	Q9Y463	349

IntAct

229 interactions, top by confidence:

A	B	Type	Score
GRB2	EGFR	psi-mi:“MI:0914”(association)	0.980
CBLB	GRB2	psi-mi:“MI:0915”(physical association)	0.970
GRB2	CBLB	psi-mi:“MI:0915”(physical association)	0.970
CBLB	GRB2	psi-mi:“MI:2364”(proximity)	0.970
CBLB	SH3KBP1	psi-mi:“MI:0915”(physical association)	0.960
CBLB	SH3KBP1	psi-mi:“MI:0407”(direct interaction)	0.960
SH3KBP1	CBLB	psi-mi:“MI:0407”(direct interaction)	0.960
SH3KBP1	CBLB	psi-mi:“MI:0915”(physical association)	0.960

BioGRID (200): SIRT2 (Affinity Capture-Western), GRB2 (Two-hybrid), NCK2 (Two-hybrid), GLRX3 (Two-hybrid), GORASP2 (Two-hybrid), UBASH3B (Two-hybrid), CBLB (Biochemical Activity), CBLB (Affinity Capture-MS), GORASP2 (Two-hybrid), CRY1 (Two-hybrid), NCK2 (Two-hybrid), SORBS3 (Two-hybrid), CBLB (Co-crystal Structure), CD2AP (Co-crystal Structure), SH3KBP1 (Reconstituted Complex)

ESM2 similar proteins: A0A0G2JTY4, A2VD01, A5PMU4, A8E4V2, D2HNW6, E1BEQ5, O54972, O95644, P16236, P59281, P70365, P97305, Q12968, Q13191, Q13469, Q13905, Q15788, Q1LY51, Q2VPU4, Q3LRZ1, Q3TTA7, Q3U182, Q4PJW2, Q4VCS5, Q60591, Q61122, Q66IV1, Q68FF7, Q6DFR2, Q6GQL0, Q6NYU6, Q6ZNC4, Q80TM6, Q80VG1, Q8HWS3, Q8IXK0, Q8IY63, Q8K4S7, Q8N228, Q8VHG2

Diamond homologs: G3V8H4, P22681, P22682, P23092, Q13191, Q3TTA7, Q6DFR2, Q6GQL0, Q6NRE7, Q80XL1, Q8K4S7, Q9ULV8, A0A1L8FG46, A0A1L8FM16, B1AUE5, C0HBT3, C0HKD7, D2H0Y8, E1B7X3, O60683, O64425, P87176, P93030, Q09463, Q1ACD5, Q28GL3, Q2PFU6, Q3T139, Q3UF64, Q587N7, Q5C8U1, Q5C8U3, Q5C8U4, Q5D7H8, Q5D7I2, Q5D7I3, Q5D7I5, Q5D7J2, Q5M7Z0, Q5REL3

SIGNOR signaling

20 interactions.

A	Effect	B	Mechanism
CBLB	“up-regulates activity”	GRB2	binding
CBLB	“up-regulates activity”	NCK1	binding
CBLB	“down-regulates activity”	EGFR	ubiquitination
CBLB	“down-regulates activity”	KIT	ubiquitination
CBLB	“up-regulates activity”	TP53
Ub:E2	“up-regulates activity”	CBLB	ubiquitination
CBLB	“down-regulates activity”	PIK3R2	ubiquitination
CBLB	“down-regulates quantity by destabilization”	PIK3R1	polyubiquitination
CBLB	“down-regulates quantity by destabilization”	EGFR	polyubiquitination
CBLB	“down-regulates quantity by destabilization”	IGF1R	ubiquitination
CBLB	“down-regulates quantity by destabilization”	CLEC6A	ubiquitination
CBLB	“down-regulates quantity”	NTRK1	ubiquitination
CBLB	“down-regulates quantity”	SYK	ubiquitination
CBLB	“down-regulates quantity”	STAT6	ubiquitination
CBLB	“up-regulates activity”	TYRO3	ubiquitination
TYRO3	“up-regulates activity”	CBLB	phosphorylation
SPRY2	down-regulates	CBLB	binding
CBLB	“down-regulates activity”	FLT3	ubiquitination

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 65 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
Regulation of signaling by CBL	6	58.4×	5e-08
Downstream signal transduction	7	52.2×	1e-08
Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants	5	50.9×	2e-06
Nephrin family interactions	5	46.6×	3e-06
RHOU GTPase cycle	7	38.2×	5e-08
FCGR3A-mediated phagocytosis	10	36.7×	4e-11
DAP12 signaling	5	36.1×	1e-05
Signaling by CSF1 (M-CSF) in myeloid cells	5	33.9×	1e-05

GO biological processes:

GO term	Partners	Fold	FDR
ephrin receptor signaling pathway	7	40.8×	3e-07
cellular response to transforming growth factor beta stimulus	5	23.4×	3e-04
epidermal growth factor receptor signaling pathway	5	21.0×	5e-04
protein autophosphorylation	5	12.3×	3e-03
cell migration	10	10.4×	1e-05
positive regulation of ERK1 and ERK2 cascade	7	10.1×	6e-04
actin filament organization	5	10.1×	5e-03
positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction	6	8.0×	4e-03

Disease & clinical

Cancer significance

From intOGen — cancer-driver classification: activating (oncogene-like) across 2 cancer types — LUAD, NSCLC.

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	3
Likely pathogenic	1
Uncertain significance	96
Likely benign	5
Benign	13

Top pathogenic / likely-pathogenic (4)

Variant ID	HGVS	Classification
2506976	NM_170662.5(CBLB):c.770A>T (p.His257Leu)	Pathogenic
2506977	NM_170662.5(CBLB):c.1402C>T (p.Arg468Ter)	Pathogenic
2506978	NM_170662.5(CBLB):c.1308C>G (p.Cys436Trp)	Pathogenic
4849425	NM_170662.5(CBLB):c.2689+2del	Likely pathogenic

SpliceAI

3900 predictions. Top by Δscore:

Variant	Effect	Δscore
3:105670228:CTCA:C	donor_loss	1.0000
3:105670229:TCACC:T	donor_loss	1.0000
3:105670230:CACCT:C	donor_loss	1.0000
3:105670231:ACCTG:A	donor_loss	1.0000
3:105670353:C:A	acceptor_loss	1.0000
3:105670353:C:CC	acceptor_gain	1.0000
3:105670354:T:C	acceptor_gain	1.0000
3:105681515:T:TA	donor_gain	1.0000
3:105693492:A:AC	donor_gain	1.0000
3:105693493:C:CC	donor_gain	1.0000
3:105720250:CCTAA:C	acceptor_loss	1.0000
3:105720251:CT:C	acceptor_loss	1.0000
3:105720252:T:C	acceptor_loss	1.0000
3:105734148:T:C	acceptor_gain	1.0000
3:105737165:CCTTA:C	donor_loss	1.0000
3:105737166:CTTAC:C	donor_loss	1.0000
3:105737167:TTA:T	donor_loss	1.0000
3:105737168:TA:T	donor_loss	1.0000
3:105737170:CC:C	donor_loss	1.0000
3:105737242:C:CT	acceptor_gain	1.0000
3:105737254:GATAA:G	acceptor_gain	1.0000
3:105737256:TAA:T	acceptor_gain	1.0000
3:105737256:TAAC:T	acceptor_loss	1.0000
3:105737257:AA:A	acceptor_gain	1.0000
3:105737259:C:CC	acceptor_gain	1.0000
3:105740488:A:AC	donor_gain	1.0000
3:105740488:ACTT:A	donor_loss	1.0000
3:105740489:C:CC	donor_gain	1.0000
3:105740489:CTT:C	donor_loss	1.0000
3:105740490:TT:T	donor_loss	1.0000

AlphaMissense

6425 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:105659009:A:C	F970L	1.000
3:105659009:A:T	F970L	1.000
3:105659011:A:G	F970L	1.000
3:105659019:A:G	L967P	1.000
3:105659019:A:T	L967H	1.000
3:105659022:A:T	I966N	1.000
3:105659031:G:T	A963D	1.000
3:105659052:G:T	A956D	1.000
3:105659061:A:G	L953S	1.000
3:105659064:G:T	A952D	1.000
3:105659103:A:G	L939P	1.000
3:105720176:A:C	F426L	1.000
3:105720176:A:T	F426L	1.000
3:105720177:A:G	F426S	1.000
3:105720178:A:G	F426L	1.000
3:105720186:A:T	V423E	1.000
3:105720192:A:C	I421R	1.000
3:105720192:A:T	I421K	1.000
3:105720210:A:C	I415R	1.000
3:105720210:A:T	I415K	1.000
3:105720219:C:G	R412P	1.000
3:105720220:G:T	R412S	1.000
3:105720221:A:C	C411W	1.000
3:105720222:C:A	C411F	1.000
3:105720222:C:G	C411S	1.000
3:105720222:C:T	C411Y	1.000
3:105720223:A:G	C411R	1.000
3:105720223:A:T	C411S	1.000
3:105720224:G:C	F410L	1.000
3:105720224:G:T	F410L	1.000

dbSNP variants (sampled 300 via entrez): RS1000002359 (3:105744134 G>A), RS1000016339 (3:105835152 G>A), RS1000018822 (3:105828486 C>A,G,T), RS1000033250 (3:105863926 A>G), RS1000039636 (3:105748149 A>T), RS1000051842 (3:105853891 C>A,T), RS1000062289 (3:105666055 A>C), RS1000068949 (3:105708157 T>G), RS1000086477 (3:105660931 A>C), RS1000089011 (3:105666248 T>G), RS1000118415 (3:105829230 A>T), RS1000124135 (3:105762988 C>A,T), RS1000158633 (3:105721517 G>C,T), RS1000169592 (3:105732310 C>T), RS1000179077 (3:105691292 C>A,T)

Disease associations

OMIM: gene MIM:604491 | disease phenotypes: MIM:620430

GenCC curated gene-disease

Disease	Classification	Inheritance
autoimmune disease, multisystem, infantile-onset, 3	Strong	Autosomal recessive

Mondo (1): autoimmune disease, multisystem, infantile-onset, 3 (MONDO:0957388)

Orphanet (0):

HPO phenotypes

22 total (22 of 22 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000403	Recurrent otitis media
HP:0000821	Hypothyroidism
HP:0001025	Urticaria
HP:0001045	Vitiligo
HP:0001890	Autoimmune hemolytic anemia
HP:0001954	Recurrent fever
HP:0002720	Decreased circulating IgA concentration
HP:0002783	Recurrent lower respiratory tract infections
HP:0002850	Decreased circulating total IgM
HP:0003593	Infantile onset
HP:0004315	Decreased circulating IgG concentration
HP:0010975	Abnormal B cell count
HP:0011463	Childhood onset
HP:0011839	Abnormal total T cell count
HP:0012476	Decreased specific pneumococcal antibody level
HP:0030783	Increased circulating interleukin 6 concentration
HP:0033199	Increased circulating interleukin 10 concentration
HP:0034797	Hepatic hemophagocytosis
HP:0040089	Abnormal total natural killer cell count
HP:0100651	Type I diabetes mellitus
HP:0410297	Partial absence of specific antibody response to tetanus vaccine

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4879459 (SINGLE PROTEIN)

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — E3 ubiquitin ligase components

Most potent curated ligand interactions (1 total), top 1:

Ligand	Action	Affinity	Parameter
NX-1607	Inhibition	7.7	pIC50

Binding affinities (BindingDB)

673 measured of 1092 human assays (1092 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
4-[(4-{3-[(4-methyl-1,2,4-triazol-3-yl)methyl]oxetan-3-yl}-6-(6-{[(3S)-3-methylpiperidin-1-yl]methyl}-1-oxo-4-(trifluoromethyl)-3H-isoindol-2-yl)pyridin-2-yl)oxy]butanenitrile	IC50	3 nM	US-20250304563: ACTIVATORS OF EFFECTOR T CELLS
3-(2,5-dioxopyrrol-1-yl)-N-[2-[2-[2-[2-[[6-[5-[[(3S)-3-methylpiperidin-1-yl]methyl]-3-oxo-7-(trifluoromethyl)-1H-isoindol-2-yl]-4-[3-[(4-methyl-1,2,4-triazol-3-yl)methyl]oxetan-3-yl]-2-pyridinyl]oxy]ethoxy]ethoxy]ethoxy]ethyl]propanamide	IC50	3 nM	US-20250304563: ACTIVATORS OF EFFECTOR T CELLS
3-methyl-2-[[6-[5-[[(3S)-3-methylpiperidin-1-yl]methyl]-3-oxo-7-(trifluoromethyl)-1H-isoindol-2-yl]-4-[3-[(4-methyl-1,2,4-triazol-3-yl)methyl]oxetan-3-yl]-2-pyridinyl]oxy]butanenitrile	IC50	3 nM	US-20250304563: ACTIVATORS OF EFFECTOR T CELLS
2-[6-(ethylamino)-4-[3-[(4-methyl-1,2,4-triazol-3-yl)methyl]oxetan-3-yl]-2-pyridinyl]-6-[[(3S)-3-methylpiperidin-1-yl]methyl]-4-methylsulfanyl-3H-isoindol-1-one	IC50	3 nM	US-20250304563: ACTIVATORS OF EFFECTOR T CELLS
6-[[(3S)-3-methylpiperidin-1-yl]methyl]-2-[4-[3-[(4-methyl-1,2,4-triazol-3-yl)methyl]oxetan-3-yl]-6-(2-sulfanylethylamino)-2-pyridinyl]-4-(trifluoromethyl)-3H-isoindol-1-one	IC50	3 nM	US-20250304563: ACTIVATORS OF EFFECTOR T CELLS
3-[[6-[5-[[(3S)-3-methylpiperidin-1-yl]methyl]-3-oxo-7-(trifluoromethyl)-1H-isoindol-2-yl]-4-[(4-methyl-1,2,4-triazol-3-yl)methoxy]-2-pyridinyl]amino]propanenitrile	IC50	3 nM	US-20250304563: ACTIVATORS OF EFFECTOR T CELLS
4-[[6-[5-[[(3S)-3-methylpiperidin-1-yl]methyl]-3-oxo-7-(trifluoromethyl)-1H-isoindol-2-yl]-4-[3-[(4-methyl-1,2,4-triazol-3-yl)methyl]oxetan-3-yl]-2-pyridinyl]amino]butanenitrile	IC50	3 nM	US-20250304563: ACTIVATORS OF EFFECTOR T CELLS
2-[6-(2-aminoethylamino)-4-[3-[(4-methyl-1,2,4-triazol-3-yl)methyl]oxetan-3-yl]-2-pyridinyl]-6-[[(3S)-3-methylpiperidin-1-yl]methyl]-4-(trifluoromethyl)-3H-isoindol-1-one	IC50	3 nM	US-20250304563: ACTIVATORS OF EFFECTOR T CELLS
2-[[6-[5-[[(3S)-3-methylpiperidin-1-yl]methyl]-3-oxo-7-(trifluoromethyl)-1H-isoindol-2-yl]-4-[3-[(4-methyl-1,2,4-triazol-3-yl)methyl]oxetan-3-yl]-2-pyridinyl]amino]acetonitrile	IC50	3 nM	US-20250304563: ACTIVATORS OF EFFECTOR T CELLS
3-[[6-[5-[[(3S)-3-methylpiperidin-1-yl]methyl]-7-methylsulfanyl-3-oxo-1H-isoindol-2-yl]-4-[3-[(4-methyl-1,2,4-triazol-3-yl)methyl]oxetan-3-yl]-2-pyridinyl]amino]propanenitrile	IC50	3 nM	US-20250304563: ACTIVATORS OF EFFECTOR T CELLS
3-[[6-[5-[(4-cyclopropyl-4-hydroxypiperidin-1-yl)methyl]-3-oxo-7-(trifluoromethyl)-1H-isoindol-2-yl]-4-[3-[(4-methyl-1,2,4-triazol-3-yl)methyl]oxetan-3-yl]-2-pyridinyl]amino]propanenitrile	IC50	3 nM	US-20250304563: ACTIVATORS OF EFFECTOR T CELLS
3-[[6-[5-[[(3aR,7aS)-5-hydroxy-1,3,3a,4,5,6,7,7a-octahydroisoindol-2-yl]methyl]-3-oxo-7-(trifluoromethyl)-1H-isoindol-2-yl]-4-[3-[(4-methyl-1,2,4-triazol-3-yl)methyl]oxetan-3-yl]-2-pyridinyl]amino]propanenitrile	IC50	3 nM	US-20250304563: ACTIVATORS OF EFFECTOR T CELLS
3-[[6-[5-[[2-(hydroxymethyl)-6-azaspiro[2.5]octan-6-yl]methyl]-3-oxo-7-(trifluoromethyl)-1H-isoindol-2-yl]-4-[3-[(4-methyl-1,2,4-triazol-3-yl)methyl]oxetan-3-yl]-2-pyridinyl]amino]propanenitrile	IC50	3 nM	US-20250304563: ACTIVATORS OF EFFECTOR T CELLS
2-[6-(2-azidoethylamino)-4-[3-[(4-methyl-1,2,4-triazol-3-yl)methyl]oxetan-3-yl]-2-pyridinyl]-6-[[(3S)-3-methylpiperidin-1-yl]methyl]-4-methylsulfanyl-3H-isoindol-1-one	IC50	3 nM	US-20250304563: ACTIVATORS OF EFFECTOR T CELLS
6-[2-hydroxy-1-[(3S)-3-methylpiperidin-1-yl]ethyl]-2-[3-[3-methyl-1-[(4-methyl-1,2,4-triazol-3-yl)methyl]cyclobutyl]phenyl]-4-(trifluoromethyl)-3H-isoindol-1-one	IC50	3 nM	US-20250304563: ACTIVATORS OF EFFECTOR T CELLS
2-[3-[3-methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]phenyl]-6-[[(3S)-3-methylpiperidin-1-yl]methyl]-4-methylsulfanyl-3H-isoindol-1-one	IC50	3 nM	US-20250304563: ACTIVATORS OF EFFECTOR T CELLS
6-[2-hydroxy-1-[(3S)-3-methylpiperidin-1-yl]ethyl]-2-[3-[3-methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]phenyl]-4-methylsulfanyl-3H-isoindol-1-one	IC50	3 nM	US-20250304563: ACTIVATORS OF EFFECTOR T CELLS
2-[6-(ethylamino)-4-[3-methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]-2-pyridinyl]-6-[[(3S)-3-methylpiperidin-1-yl]methyl]-4-methylsulfanyl-3H-isoindol-1-one	IC50	3 nM	US-20250304563: ACTIVATORS OF EFFECTOR T CELLS
2-[6-amino-4-[3-[(4-methyl-1,2,4-triazol-3-yl)methyl]oxetan-3-yl]-2-pyridinyl]-6-[[(3S)-3-methylpiperidin-1-yl]methyl]-4-methylsulfanyl-3H-isoindol-1-one	IC50	3 nM	US-20250304563: ACTIVATORS OF EFFECTOR T CELLS
2-[6-(ethylamino)-4-[3-[(4-methyl-1,2,4-triazol-3-yl)methyl]oxetan-3-yl]-2-pyridinyl]-4-methylsulfanyl-6-(piperidin-1-ylmethyl)-3H-isoindol-1-one	IC50	3 nM	US-20250304563: ACTIVATORS OF EFFECTOR T CELLS
3-[[6-[7-formyl-5-[[(3S)-3-methylpiperidin-1-yl]methyl]-3-oxo-1H-isoindol-2-yl]-4-[3-[(4-methyl-1,2,4-triazol-3-yl)methyl]oxetan-3-yl]-2-pyridinyl]amino]propanenitrile	IC50	3 nM	US-20250304563: ACTIVATORS OF EFFECTOR T CELLS
(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

ChEMBL bioactivities

1006 potent at pChembl≥5 of 1050 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
9.52	Ki	0.3	nM	CHEMBL6134621
9.40	Ki	0.4	nM	CHEMBL6103468
9.30	Ki	0.5	nM	CHEMBL6120549
9.13	Ki	0.74	nM	CHEMBL6190017
9.10	Ki	0.8	nM	CHEMBL6191789
9.09	Ki	0.82	nM	CHEMBL6190800
9.08	Ki	0.83	nM	CHEMBL6191422
9.08	Ki	0.84	nM	CHEMBL6189518
9.07	Ki	0.86	nM	CHEMBL6189396
9.07	Ki	0.86	nM	CHEMBL6188556
9.05	Ki	0.9	nM	CHEMBL6147468
9.02	Ki	0.96	nM	CHEMBL6188747
9.01	Ki	0.97	nM	CHEMBL6190350
9.00	IC50	1	nM	CHEMBL5573196
9.00	IC50	1	nM	CHEMBL5568649
9.00	Ki	1	nM	CHEMBL6133335
8.99	Ki	1.02	nM	CHEMBL6190612
8.96	Ki	1.1	nM	CHEMBL6102700
8.96	Ki	1.1	nM	CHEMBL6189291
8.95	Ki	1.13	nM	CHEMBL6192793
8.94	Ki	1.14	nM	CHEMBL6192645
8.94	Ki	1.16	nM	CHEMBL6191987
8.93	Ki	1.18	nM	CHEMBL6193033
8.92	Ki	1.2	nM	CHEMBL6134158
8.92	Ki	1.2	nM	CHEMBL6188701
8.91	Ki	1.22	nM	CHEMBL6192094
8.90	Ki	1.25	nM	CHEMBL6189401
8.88	Ki	1.32	nM	CHEMBL6188729
8.87	Ki	1.35	nM	CHEMBL6188566
8.87	Ki	1.34	nM	CHEMBL6191835
8.86	Ki	1.39	nM	CHEMBL6191550
8.85	Ki	1.4	nM	CHEMBL6147378
8.85	Ki	1.43	nM	CHEMBL6191518
8.85	Ki	1.4	nM	CHEMBL6193311
8.85	Ki	1.41	nM	CHEMBL6189814
8.85	Ki	1.4	nM	CHEMBL6188408
8.84	Ki	1.45	nM	CHEMBL6190745
8.83	Ki	1.47	nM	CHEMBL6193296
8.82	IC50	1.5	nM	CHEMBL6004414
8.82	IC50	1.5	nM	CHEMBL5962244
8.82	IC50	1.5	nM	CHEMBL6026052
8.82	IC50	1.5	nM	CHEMBL5858130
8.82	IC50	1.5	nM	CHEMBL5800056
8.82	IC50	1.5	nM	CHEMBL5769042
8.82	IC50	1.5	nM	CHEMBL5889777
8.82	IC50	1.5	nM	CHEMBL5995253
8.82	IC50	1.5	nM	CHEMBL5936693
8.82	IC50	1.5	nM	CHEMBL5990180
8.81	Ki	1.54	nM	CHEMBL6192261
8.80	Ki	1.6	nM	CHEMBL6141556

PubChem BioAssay actives

174 with measured affinity, of 272 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
2-[1-[[2-[3-[3-[(4-methyl-1,2,4-triazol-3-yl)methyl]oxetan-3-yl]phenyl]-3-oxo-7-(trifluoromethyl)-1H-isoindol-5-yl]methyl]piperidin-3-yl]acetonitrile	2098222: Inhibition of N-terminal biotinylated Avi-tagged Cbl-b (36 to 427 residues) (unknown origin) by SPR assay	ic50	0.0010	uM
3-[3-[5-[[(3S)-3-methylpiperidin-1-yl]methyl]-3-oxo-7-(trifluoromethyl)-1H-isoindol-2-yl]phenyl]-3-[(4-methyl-1,2,4-triazol-3-yl)methyl]cyclobutane-1-carbonitrile	2098222: Inhibition of N-terminal biotinylated Avi-tagged Cbl-b (36 to 427 residues) (unknown origin) by SPR assay	ic50	0.0010	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	2107206: Inhibition of N-terminal His-tagged human Cbl-b (40 to 426 residues) expressed in Escherichia coli by measured for 90 mins by HTRF method	ic50	0.0010	uM
2-[3-[3-methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]phenyl]-6-[[(3S)-3-methylpiperidin-1-yl]methyl]-4-(trifluoromethyl)-3H-isoindol-1-one	2038989: Binding affinity to avidin-biotinylated Cbl-b at (36 to 427 residues) (unknown origin) assessed as dissociation constant by SPR analysis	kd	0.0030	uM
2-[3-[[3-[5-[[(1-methylcyclobutyl)amino]methyl]-3-oxo-7-(trifluoromethyl)-1H-isoindol-2-yl]phenyl]-(4-methyl-1,2,4-triazol-3-yl)methyl]cyclobutyl]acetonitrile	2010112: Inhibition of biotin-tagged Cbl-b (unknown origin) assessed as reduction in LCK ubiquitination using His-LCK as substrate preincubated for 60 mins followed by substrate addition in presence of ATP, MgCl2 and measured after 90 mins by HTRF assay	ic50	0.0030	uM
2-[6-ethoxy-4-[3-methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]-2-pyridinyl]-6-[[(1-methylcyclobutyl)amino]methyl]-4-(trifluoromethyl)-3H-isoindol-1-one	2010112: Inhibition of biotin-tagged Cbl-b (unknown origin) assessed as reduction in LCK ubiquitination using His-LCK as substrate preincubated for 60 mins followed by substrate addition in presence of ATP, MgCl2 and measured after 90 mins by HTRF assay	ic50	0.0040	uM
4-chloro-2-[3-[3-fluoro-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]phenyl]-6-[(1S)-1-[(1-methylcyclobutyl)amino]ethyl]-3H-isoindol-1-one	2010112: Inhibition of biotin-tagged Cbl-b (unknown origin) assessed as reduction in LCK ubiquitination using His-LCK as substrate preincubated for 60 mins followed by substrate addition in presence of ATP, MgCl2 and measured after 90 mins by HTRF assay	ic50	0.0040	uM
2-[3-[3-chloro-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]phenyl]-6-[[(1-methylcyclobutyl)amino]methyl]-4-(trifluoromethyl)-3H-isoindol-1-one	2010112: Inhibition of biotin-tagged Cbl-b (unknown origin) assessed as reduction in LCK ubiquitination using His-LCK as substrate preincubated for 60 mins followed by substrate addition in presence of ATP, MgCl2 and measured after 90 mins by HTRF assay	ic50	0.0040	uM
6-[(1S)-1-[(1-methylcyclobutyl)amino]ethyl]-2-[3-[(S)-(4-methyl-1,2,4-triazol-3-yl)-(oxetan-3-yl)methyl]phenyl]-4-(trifluoromethyl)-3H-isoindol-1-one	2010112: Inhibition of biotin-tagged Cbl-b (unknown origin) assessed as reduction in LCK ubiquitination using His-LCK as substrate preincubated for 60 mins followed by substrate addition in presence of ATP, MgCl2 and measured after 90 mins by HTRF assay	ic50	0.0040	uM
6-[(3-bicyclo[3.1.0]hexanylamino)methyl]-2-[3-[3-methoxy-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]phenyl]-4-(trifluoromethyl)-3H-isoindol-1-one	2010112: Inhibition of biotin-tagged Cbl-b (unknown origin) assessed as reduction in LCK ubiquitination using His-LCK as substrate preincubated for 60 mins followed by substrate addition in presence of ATP, MgCl2 and measured after 90 mins by HTRF assay	ic50	0.0040	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	2107193: Inhibition of Cbl-b (unknown origin) by SPR assay	ic50	0.0040	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	2107206: Inhibition of N-terminal His-tagged human Cbl-b (40 to 426 residues) expressed in Escherichia coli by measured for 90 mins by HTRF method	ic50	0.0040	uM
2-[6-cyclopentyloxy-4-[3-[(4-methyl-1,2,4-triazol-3-yl)methyl]oxetan-3-yl]-2-pyridinyl]-6-[[(2R)-4-methyl-2-propan-2-ylpiperazin-1-yl]methyl]-4-(trifluoromethyl)-3H-isoindol-1-one	1865534: Inhibition of Cbl-b (unknown origin) assessed as reduction in LCK ubiquitination preincubated for 60 mins followed by kinase mix addition measured after 90 mins by TR-FRET assay	ic50	0.0055	uM
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	1865534: Inhibition of Cbl-b (unknown origin) assessed as reduction in LCK ubiquitination preincubated for 60 mins followed by kinase mix addition measured after 90 mins by TR-FRET assay	ic50	0.0056	uM
2-[3-[3,3-difluoro-1-[(4-methyl-1,2,4-triazol-3-yl)methyl]cyclobutyl]phenyl]-6-[(1R)-1-[(1-methylcyclobutyl)amino]ethyl]-4-(trifluoromethyl)-3H-isoindol-1-one	1865534: Inhibition of Cbl-b (unknown origin) assessed as reduction in LCK ubiquitination preincubated for 60 mins followed by kinase mix addition measured after 90 mins by TR-FRET assay	ic50	0.0058	uM
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	1865534: Inhibition of Cbl-b (unknown origin) assessed as reduction in LCK ubiquitination preincubated for 60 mins followed by kinase mix addition measured after 90 mins by TR-FRET assay	ic50	0.0060	uM
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	1865534: Inhibition of Cbl-b (unknown origin) assessed as reduction in LCK ubiquitination preincubated for 60 mins followed by kinase mix addition measured after 90 mins by TR-FRET assay	ic50	0.0064	uM
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	1865534: Inhibition of Cbl-b (unknown origin) assessed as reduction in LCK ubiquitination preincubated for 60 mins followed by kinase mix addition measured after 90 mins by TR-FRET assay	ic50	0.0067	uM
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	2107192: Inhibition of Cbl-b (unknown origin) ubiquitination by TR-FRET assay	ic50	0.0070	uM
(6R)-6-cyclopropyl-6-[3-[6-[[(3S)-3-methylpiperidin-1-yl]methyl]-3-oxo-8-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-2-yl]phenyl]-1,3-oxazinan-2-one	2114743: Inhibition of Cbl-b (unknown origin) by TR-FRET assay	ic50	0.0070	uM
8-methyl-6-[[(1-methylcyclobutyl)amino]methyl]-3-[3-[3-methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]phenyl]chromen-4-one	2107194: Inhibition of Cbl-b (unknown origin)	ic50	0.0100	uM
2-[[(2R)-2-methylmorpholin-4-yl]methyl]-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]benzamide	2038987: Displacement of FAM-labeled probe from recombinant biotinylated Cbl-b (unknown origin) expressed in Escherichia coli BL21(DE3) Tuner cells by TR-FRET assay	ic50	0.0100	uM
2-[3-[3-methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]phenyl]-6-[[(3S)-3-methylpiperidin-1-yl]methyl]-8-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-3-one	2114743: Inhibition of Cbl-b (unknown origin) by TR-FRET assay	ic50	0.0110	uM
(3S)-N-(2-methoxyethyl)-3-[[2-[[(2S)-2-methylmorpholin-4-yl]methyl]benzoyl]amino]-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-8-carboxamide	2038987: Displacement of FAM-labeled probe from recombinant biotinylated Cbl-b (unknown origin) expressed in Escherichia coli BL21(DE3) Tuner cells by TR-FRET assay	ic50	0.0130	uM
2-[[(2S)-2-methylmorpholin-4-yl]methyl]-N-[(3S)-8-(4-methyl-3-oxopiperazine-1-carbonyl)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]benzamide	2038987: Displacement of FAM-labeled probe from recombinant biotinylated Cbl-b (unknown origin) expressed in Escherichia coli BL21(DE3) Tuner cells by TR-FRET assay	ic50	0.0130	uM
2-[[(2S)-2-methylmorpholin-4-yl]methyl]-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]benzamide	2038987: Displacement of FAM-labeled probe from recombinant biotinylated Cbl-b (unknown origin) expressed in Escherichia coli BL21(DE3) Tuner cells by TR-FRET assay	ic50	0.0130	uM
2-[[(2S)-2-methylmorpholin-4-yl]methyl]-N-[(3S)-2-oxo-5-phenyl-1,3-dihydropyrido[3,4-e][1,4]diazepin-3-yl]benzamide	2038987: Displacement of FAM-labeled probe from recombinant biotinylated Cbl-b (unknown origin) expressed in Escherichia coli BL21(DE3) Tuner cells by TR-FRET assay	ic50	0.0150	uM
2-cyclopropyl-6-methyl-N-[3-[3-[(4-methyl-1,2,4-triazol-3-yl)methyl]oxetan-3-yl]phenyl]pyrimidine-4-carboxamide	2107195: Inhibition of Cbl-b (unknown origin) by TR-FRET assay	ic50	0.0200	uM
7-[(1-methyl-3-azabicyclo[3.1.1]heptan-3-yl)methyl]-3-[3-[3-methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]phenyl]-9-(trifluoromethyl)pyrido[1,2-a]pyrimidin-4-one	2107194: Inhibition of Cbl-b (unknown origin)	ic50	0.0200	uM
4-[[(1-methylcyclobutyl)amino]methyl]-1-[3-[3-methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]phenyl]benzo[cd]indol-2-one	2107193: Inhibition of Cbl-b (unknown origin) by SPR assay	ic50	0.0200	uM
2-[[(2S)-2-methylmorpholin-4-yl]methyl]-N-(2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl)benzamide	2038987: Displacement of FAM-labeled probe from recombinant biotinylated Cbl-b (unknown origin) expressed in Escherichia coli BL21(DE3) Tuner cells by TR-FRET assay	ic50	0.0260	uM
12-[3-[(2S)-2-[[6-oxo-5-(trifluoromethyl)-1H-pyridazin-4-yl]amino]propoxy]propanoyl]-5-(trifluoromethyl)-1,3,8,12-tetrazatricyclo[8.4.0.02,7]tetradeca-2(7),3,5-trien-9-one	2098922: Inhibition of biotinylated recombinant Cbl-b (36 to 427 residues)(unknown origin) expressed in Escherichia coli BL21(DE3) Tuner cells assessed as decrease in ZAP70 ubiquitination incubated for 60 mins in presence of Ub-FITC/ATP by TR-FRET assay	ic50	0.0269	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	2098911: Inhibition of biotinylated recombinant Cbl-b (36 to 427 residues)(unknown origin) expressed in Escherichia coli BL21(DE3) Tuner cells using a FAM-labeled probe by TR-FRET assay	ic50	0.0300	uM
3-[3-[3-methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]phenyl]-1-[(2S)-pent-3-yn-2-yl]-5-(trifluoromethyl)pyridin-2-one	2098911: Inhibition of biotinylated recombinant Cbl-b (36 to 427 residues)(unknown origin) expressed in Escherichia coli BL21(DE3) Tuner cells using a FAM-labeled probe by TR-FRET assay	ic50	0.0300	uM
3-[3-[3-methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]phenyl]-1-[(1-methyltriazol-4-yl)methyl]-5-(trifluoromethyl)pyridin-2-one	2098911: Inhibition of biotinylated recombinant Cbl-b (36 to 427 residues)(unknown origin) expressed in Escherichia coli BL21(DE3) Tuner cells using a FAM-labeled probe by TR-FRET assay	ic50	0.0300	uM
2-[[(2R)-2-methylmorpholin-4-yl]methyl]-N-(2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl)benzamide	2038987: Displacement of FAM-labeled probe from recombinant biotinylated Cbl-b (unknown origin) expressed in Escherichia coli BL21(DE3) Tuner cells by TR-FRET assay	ic50	0.0310	uM
1-but-2-ynyl-3-[3-[3-methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]phenyl]-5-(trifluoromethyl)pyridin-2-one	2098911: Inhibition of biotinylated recombinant Cbl-b (36 to 427 residues)(unknown origin) expressed in Escherichia coli BL21(DE3) Tuner cells using a FAM-labeled probe by TR-FRET assay	ic50	0.0340	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	2098223: Inhibition of Cbl-b (unknown origin) by TR-FRET assay	ic50	0.0360	uM
2-cyclopropyl-6-methyl-N-[3-[(2R)-1-(4-methyl-1,2,4-triazol-3-yl)propan-2-yl]phenyl]pyrimidine-4-carboxamide	2098217: Inhibition of CBL-B (unknown origin) by FRET assay	ic50	0.0380	uM
3-[3-[3-methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]phenyl]-1-[(1R)-1-(1-methylpyrazol-4-yl)ethyl]-5-(trifluoromethyl)pyridin-2-one	2098911: Inhibition of biotinylated recombinant Cbl-b (36 to 427 residues)(unknown origin) expressed in Escherichia coli BL21(DE3) Tuner cells using a FAM-labeled probe by TR-FRET assay	ic50	0.0400	uM
(2S)-2-[3-[3-[3-methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]phenyl]-2-oxo-5-(trifluoromethyl)-1-pyridinyl]propanenitrile	2098911: Inhibition of biotinylated recombinant Cbl-b (36 to 427 residues)(unknown origin) expressed in Escherichia coli BL21(DE3) Tuner cells using a FAM-labeled probe by TR-FRET assay	ic50	0.0400	uM
3-[3-[3-methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]phenyl]-1-[(1-methylpyrazol-4-yl)methyl]-5-(trifluoromethyl)pyridin-2-one	2098911: Inhibition of biotinylated recombinant Cbl-b (36 to 427 residues)(unknown origin) expressed in Escherichia coli BL21(DE3) Tuner cells using a FAM-labeled probe by TR-FRET assay	ic50	0.0400	uM
2-[7-methoxy-2-[2-[(1S,3S)-1-methyl-3-(2-methyl-5-nitrophenyl)-5-oxo-1,3-dihydroimidazo[1,5-a]pyridin-2-yl]-2-oxoethoxy]quinolin-8-yl]acetic acid	2094882: Binding affinity to N-terminal Avi-tagged biotinylated human Cbl-b (40 to 426 residues) expressed in Escherichia coli by SPR assay	kd	0.0440	uM
3-[3-[3-methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]phenyl]-1-[[(3S)-1-methylpyrrolidin-3-yl]methyl]-5-(trifluoromethyl)pyridin-2-one	2098911: Inhibition of biotinylated recombinant Cbl-b (36 to 427 residues)(unknown origin) expressed in Escherichia coli BL21(DE3) Tuner cells using a FAM-labeled probe by TR-FRET assay	ic50	0.0500	uM
1-[(1-methylimidazol-4-yl)methyl]-3-[3-[3-methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]phenyl]-5-(trifluoromethyl)pyridin-2-one	2098911: Inhibition of biotinylated recombinant Cbl-b (36 to 427 residues)(unknown origin) expressed in Escherichia coli BL21(DE3) Tuner cells using a FAM-labeled probe by TR-FRET assay	ic50	0.0500	uM
3-[3-[(R)-cyclobutyl-(4-methyl-1,2,4-triazol-3-yl)methyl]phenyl]-5-(trifluoromethyl)-1H-pyridin-2-one	2098911: Inhibition of biotinylated recombinant Cbl-b (36 to 427 residues)(unknown origin) expressed in Escherichia coli BL21(DE3) Tuner cells using a FAM-labeled probe by TR-FRET assay	ic50	0.0590	uM
3-[3-[3-methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]phenyl]-1-[(5-methyl-1,3,4-oxadiazol-2-yl)methyl]-5-(trifluoromethyl)pyridin-2-one	2098911: Inhibition of biotinylated recombinant Cbl-b (36 to 427 residues)(unknown origin) expressed in Escherichia coli BL21(DE3) Tuner cells using a FAM-labeled probe by TR-FRET assay	ic50	0.0700	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	2098223: Inhibition of Cbl-b (unknown origin) by TR-FRET assay	ic50	0.0720	uM
3-[3-[3-methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]phenyl]-1-[(1-methylpiperidin-4-yl)methyl]-5-(trifluoromethyl)pyridin-2-one	2098911: Inhibition of biotinylated recombinant Cbl-b (36 to 427 residues)(unknown origin) expressed in Escherichia coli BL21(DE3) Tuner cells using a FAM-labeled probe by TR-FRET assay	ic50	0.0740	uM
2-[7-methoxy-2-[2-[(1S,3S)-3-(3-methoxy-2-methyl-5-nitrophenyl)-1-methyl-5-oxo-1,3-dihydroimidazo[1,5-a]pyridin-2-yl]-2-oxoethoxy]quinolin-8-yl]acetic acid	2094882: Binding affinity to N-terminal Avi-tagged biotinylated human Cbl-b (40 to 426 residues) expressed in Escherichia coli by SPR assay	kd	0.0780	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, decreases expression, affects expression, increases expression	5
sodium arsenite	increases expression, decreases expression, increases abundance	4
trichostatin A	decreases expression, affects cotreatment	3
Aflatoxin B1	affects expression, decreases methylation	3
perfluorooctane sulfonic acid	increases expression, decreases expression	2
perfluoro-n-nonanoic acid	decreases expression, increases expression	2
Acetaminophen	affects expression, increases expression	2
Benzo(a)pyrene	decreases expression, decreases methylation	2
Copper	affects binding, decreases expression, increases expression	2
Formaldehyde	decreases expression	2
Hydrogen Peroxide	affects expression, decreases expression	2
Tobacco Smoke Pollution	increases expression	2
Cyclosporine	increases expression	2
aristolochic acid I	decreases expression	1
triphenyl phosphate	affects expression	1
alpha-pinene	affects cotreatment, increases expression, increases abundance	1
pirinixic acid	decreases expression, increases activity, affects binding	1
bisphenol A	decreases methylation	1
arsenite	decreases reaction, affects binding	1
sulforaphane	increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
cobaltous chloride	increases expression	1
butyraldehyde	decreases expression	1
perfluorooctanoic acid	decreases expression	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
4-hydroxy-2-nonenal	decreases expression	1
2,3-bis(3’-hydroxybenzyl)butyrolactone	affects cotreatment, decreases expression	1
nickel sulfate	increases expression	1
methacrylaldehyde	affects cotreatment, increases expression, increases abundance	1
epigallocatechin gallate	affects cotreatment, decreases expression, increases expression	1

ChEMBL screening assays

58 unique, capped per target: 58 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4821586	Binding	Binding affinity to recombinant His-tagged Cbl-b (unknown origin) (39 to 368 residues) expressed in Escherichia coli BL21 (DE3) using FITC-DGpYPEPA-NH2 as substrate incubated for 30 mins by fluorescence polarization assay	An affinity prediction approach for the ligand of E3 ligase Cbl-b and an insight into substrate binding pattern. — Bioorg Med Chem

Cellosaurus cell lines

5 cell lines: 4 cancer cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B1MB	Abcam HeLa CBLB KO	Cancer cell line	Female
CVCL_B8CI	Abcam HCT 116 CBLB KO	Cancer cell line	Male
CVCL_B8TD	Abcam MCF-7 CBLB KO	Cancer cell line	Female
CVCL_B9EP	Abcam A-549 CBLB KO	Cancer cell line	Male
CVCL_D9B5	Ubigene HEK293 CBLB KO	Transformed cell line	Female

Clinical trials (associated diseases)

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