VHL

Summary

VHL (von Hippel-Lindau tumor suppressor, HGNC:12687) is a protein-coding gene on chromosome 3p25.3, encoding von Hippel-Lindau disease tumor suppressor (P40337). Involved in the ubiquitination and subsequent proteasomal degradation via the von Hippel-Lindau ubiquitination complex. In precision oncology, VHL Mutation confers sensitivity to Pazopanib in Renal Cell Carcinoma (CIViC Level B); 7 further curated variant–drug associations are listed below. It is a selective cancer dependency (DepMap: 77.0% of cell lines) and haploinsufficient (ClinGen: sufficient evidence).

This gene encodes a component of a ubiquitination complex. The encoded protein is involved in the ubiquitination and degradation of hypoxia-inducible-factor (HIF), which is a transcription factor that plays a central role in the regulation of gene expression by oxygen. In addition to oxygen-related gene expression, this protein plays a role in many other cellular processes including cilia formation, cytokine signaling, regulation of senescence, and formation of the extracellular matrix. Variants of this gene are associated with von Hippel-Lindau syndrome, pheochromocytoma, erythrocytosis, renal cell carcinoma, and cerebellar hemangioblastoma.

Source: NCBI Gene 7428 — RefSeq curated summary.

At a glance

• Gene–disease (curated): von Hippel-Lindau disease (Definitive, ClinGen) — +5 more curated relationships
• GWAS associations: 2
• Clinical variants (ClinVar): 988 total — 136 pathogenic, 40 likely-pathogenic
• Phenotypes (HPO): 105
• Druggable target: yes — 7 molecules with ChEMBL bioactivity
• Precision-oncology evidence (CIViC): 8 curated variant–drug associations
• Cancer driver (intOGen): loss-of-function (tumor-suppressor-like) across 3 cancer types
• Cancer dependency (DepMap): dependent in 77.0% of screened cell lines
• Dosage sensitivity (ClinGen): haploinsufficiency sufficient evidence, triplosensitivity no evidence
• Transcription factor: yes — 25 downstream targets (CollecTRI)
• MANE Select transcript: NM_000551

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:12687
Approved symbol	VHL
Name	von Hippel-Lindau tumor suppressor
Location	3p25.3
Locus type	gene with protein product
Status	Approved
Aliases	VHL1
Ensembl gene	ENSG00000134086
Ensembl biotype	protein_coding
OMIM	608537
Entrez	7428

Gene structure

Transcript identifiers

Ensembl transcripts: 13 — 8 protein_coding, 2 retained_intron, 2 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000256474, ENST00000345392, ENST00000477538, ENST00000696142, ENST00000696143, ENST00000696153, ENST00000713811, ENST00000713812, ENST00000713813, ENST00000713814, ENST00000713815, ENST00000713816, ENST00000713982

RefSeq mRNA: 3 — MANE Select: NM_000551 NM_000551, NM_001354723, NM_198156

CCDS: CCDS2597, CCDS2598, CCDS93209

Canonical transcript exons

ENST00000256474 — 3 exons

Exon	Start	End
ENSE00001930974	10141778	10142187
ENSE00004022056	10146514	10146636
ENSE00004022057	10149787	10153667

Expression profiles

Bgee: expression breadth ubiquitous, 186 present calls, max score 94.86.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 28.7893 / max 1368.4825, expressed in 1816 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
35277	26.2849	1812
35280	1.5750	735
35278	0.5665	311
35279	0.3628	164

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
cortical plate	UBERON:0005343	94.86	gold quality
monocyte	CL:0000576	94.31	gold quality
mononuclear cell	CL:0000842	93.09	gold quality
leukocyte	CL:0000738	92.90	gold quality
ganglionic eminence	UBERON:0004023	92.23	gold quality
stromal cell of endometrium	CL:0002255	89.57	gold quality
ventricular zone	UBERON:0003053	89.00	gold quality
buccal mucosa cell	CL:0002336	87.61	gold quality
adrenal tissue	UBERON:0018303	87.40	gold quality
granulocyte	CL:0000094	87.28	gold quality
islet of Langerhans	UBERON:0000006	87.15	gold quality
lymph node	UBERON:0000029	86.73	gold quality
colonic epithelium	UBERON:0000397	86.51	gold quality
rectum	UBERON:0001052	86.47	gold quality
endometrium epithelium	UBERON:0004811	85.95	gold quality
cerebellar hemisphere	UBERON:0002245	85.80	gold quality
cerebellar cortex	UBERON:0002129	85.76	gold quality
small intestine Peyer’s patch	UBERON:0003454	85.11	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	85.05	gold quality
right hemisphere of cerebellum	UBERON:0014890	84.58	gold quality
left adrenal gland	UBERON:0001234	84.34	gold quality
spleen	UBERON:0002106	84.24	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	84.21	gold quality
right adrenal gland cortex	UBERON:0035827	84.20	gold quality
lower esophagus mucosa	UBERON:0035834	84.17	gold quality
gall bladder	UBERON:0002110	84.16	gold quality
left adrenal gland cortex	UBERON:0035825	84.16	gold quality
minor salivary gland	UBERON:0001830	83.85	gold quality
right adrenal gland	UBERON:0001233	83.70	gold quality
calcaneal tendon	UBERON:0003701	83.68	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.19
E-ENAD-27	no	3.87

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

25 targets.

Target	Regulation
ANGPT2	Repression
AR	Activation
CA12	Unknown
CA9	Unknown
CCND1	Unknown
CDH1	Unknown
CDKN1B	Activation
CDKN1C	Activation
CENPX	Unknown
COL4A2	Unknown
CXCR4	Repression
DAB2	Activation
HIF1A	Repression
IGF1R	Repression
KLF10	Unknown
NMU	Repression
PDGFB	Activation
SNAI1	Repression
SPARC	Activation
TCF4	Unknown
TFRC	Repression
TMEM115	Activation
TP53	Unknown
VEGFA	Activation
ZEB2

Upstream regulators (CollecTRI, top): E2F4, HIF1A, MYC, TP53

miRNA regulators (miRDB)

159 targeting VHL, 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-3613-3P	100.00	76.36	7965
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-29A-3P	100.00	73.11	1835
HSA-MIR-29B-3P	100.00	73.18	1833
HSA-MIR-29C-3P	100.00	73.15	1833
HSA-MIR-4673	100.00	66.64	1490
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-150-5P	99.99	66.69	1976
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-493-5P	99.96	72.47	2382
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-548AT-5P	99.96	70.83	2666
HSA-MIR-767-5P	99.95	70.85	993

Functional genomics

ClinGen dosage: haploinsufficiency 3 (sufficient evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map DepMap (CRISPR cell-line fitness): dependent in 77.0% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 40)

• Expression of the von Hippel-Lindau gene protein in breast cancer tissue. (PMID:11749004)
• VHL-dependent sensitization of RCC cells to TNF-alpha-mediated killing may contribute to VHL’s growth-suppressive function (PMID:11840338)
• Erythropoietin, tumours and the von Hippel-Lindau gene: towards identification of mechanisms and dysfunction of oxygen sensing. (PMID:11865075)
• Role in regulation of cell growth. (PMID:11908068)
• Inactivation of the VHL tumor suppressor gene is a genetic change in the tumorigenic pathway of clear-cell renal cell carcinoma and may occur at an early or first step in the tumorigenic pathway rather than as a late event. (PMID:11921283)
• The Chuvash polycythemia gene is identified as the VHL gene with a point mutation that disrupts VHL function, causing a failure to degrade HIF-1 alpha and upregulation of downstream target genes such as EPO. (PMID:11987242)
• A novel point mutation in the VHL gene (406 T–>G) was found in a patient with multiple recurrent chromaffin paragangliomas. (PMID:11990703)
• structure of an HIF-1alpha-pVHL complex determined; role of hydroxyproline (PMID:12004076)
• mutation in renal cell carcinoma (PMID:12016154)
• VHL-mediated hypoxia regulation of cyclin D1 in renal carcinoma cells. (PMID:12036906)
• molecular basis for stabilization by components of VHL ubiquitin ligase (PMID:12048197)
• crystal structure and basis for the recognition of hydroxyproline in HIF-1 alpha by pVHL (PMID:12050673)
• Down regulation of HIF-1 by VHL protein is associated with tumorigenesis of clear cell carcinoma of the kidney (PMID:12086860)
• Identification of cyclin D1 and other novel targets for the von Hippel-Lindau tumor suppressor gene by expression array analysis and investigation of cyclin D1 genotype as a modifier in von Hippel-Lindau disease. (PMID:12097293)
• Functional analysis of the VHL tumor suppressor gene promoter sheds light on the developmental regulation of VHL expression, molecular pathology of epigenetic silencing of VHL in tumorigenesis, and suggests a link between Sp1, VHL, and nephrogenesis. (PMID:12114475)
• Deletions of the entire VHL gene have occurred in von Hippel-Lindau syndrome patients from Poland. (PMID:12114495)
• VHL protein has a role in protein stabilization in human kidney (PMID:12169691)
• REVIEW: Molecular basis of the VHL hereditary cancer syndrome (PMID:12209156)
• The binding of pVHL to HIF is governed by the enzymatic hydroxylation of conserved prolyl residues within peptidic motifs present in the HIFalpha family members. (PMID:12351678)
• Review. The von Hippel-Lindau tumor suppressor protein regulates hypoxia-inducible gene transcription. It is a subunit of an E3 ubiquitin ligase targeting HIFalpha subunits. (PMID:12374282)
• Direct sequencing analyses revealed that the tumors exhibited frameshift mutations and in some cases loss of heterozygosity at the VHL gene locus. (PMID:12378530)
• propose that mutations of the VHL gene represent an important cause of pediatric sporadic polycythemias with an inappropriately high serum erythropoietin concentration (PMID:12393546)
• P81S germline mutation in a German Von Hippel-Lindau disease type 2C family with the previously identified L188V mutation; co-segregation of these two mutations with the disease (PMID:12414898)
• Von Hippel-Lindau tumor suppressor protein transforms human neuroblastoma cells into functional neuron-like cells. (PMID:12460920)
• VHL regulates protein stability and the transactivation function of the hypoxia-inducible factor-1alpha (PMID:12468553)
• HIF-1 binds to VHL in a specific binding site (PMID:12482756)
• BRCA1 AND VHL LOH is infrequent in sporadic breast carcinoma. (PMID:12490973)
• role for pVHL in the regulation of microtubule dynamics and potentially provide a link between this function of pVHL and the pathogenesis of haemangioblastoma and phaeochromocytoma in the context of VHL disease (PMID:12510195)
• models for function of this protein and Hippel-Lindau disease (PMID:12511881)
• identification of complex with E3 ligase as target of splice variants of HIF-3 alpha locus (PMID:12538644)
• mutation not a common means of VHL inactivation in non-small-cell lung cancer (PMID:12609565)
• TNF-alpha mRNA was a target of translational repression by pVHL through the TNF-alpha 3’-untranslated region in renal cell carcinoma cells (PMID:12640117)
• Mutations in Von Hippel-Lindau gene product are associated with malignant transformation of pheochromocytomas (PMID:12673678)
• demonstrate that the KRAB-A domain in VHLaK mediates pVHL binding and functions as a transcriptional repression module; findings provide a novel mechanism for the modulation of hypoxia-inducible factor-1alpha (HIF-1alpha) transactivation by pVHL (PMID:12682018)
• Germline mutation of the VHL gene and loss of heterozygosity on the VHL gene locus in 3p were detected in a meningioma in VHL disease associated with multiple cerebellar hemangioblastomas (PMID:12682336)
• Methylation inactivation of vhl is associated with oral cancer (PMID:12684640)
• To better understand the role of VHL in the hypoxia signaling pathways of tumor cells, we used serial analysis of gene expression (SAGE) to investigate hypoxia-regulated gene expression in renal carcinoma cells (786-0), with and without VHL (PMID:12692265)
• We conclude that, in vivo, folding of VHL requires the cooperation of Hsp70 and TRiC and that Hsp70 acts to promote substrate binding to TRiC. (PMID:12697815)
• Loss of this protein causes cell density dependent deregulation of CyclinD1 expression through hypoxia-inducible factor. (PMID:12743597)
• Downregulation of Cap43 gene by von Hippel-Lindau protein in renal cancer cells. (PMID:12767066)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	vhl	ENSDARG00000070617
mus_musculus	Vhl	ENSMUSG00000033933
rattus_norvegicus	Vhl	ENSRNOG00000010258
drosophila_melanogaster	Vhl	FBGN0041174

Paralogs (1): VHLL (ENSG00000189030)

Protein

Protein identifiers

von Hippel-Lindau disease tumor suppressor — P40337 (reviewed: P40337)

Alternative names: Protein G7, pVHL

All UniProt accessions (10): A0A024R2F2, A0A0S2Z4K1, A0A8Q3SIA6, A0A8Q3WL21, A0AAQ5BGZ3, A0AAQ5BGZ5, A0AAQ5BH02, A0AAQ5BH16, A0AAQ5BH56, P40337

UniProt curated annotations — full annotation on UniProt →

Function. Involved in the ubiquitination and subsequent proteasomal degradation via the von Hippel-Lindau ubiquitination complex. Seems to act as a target recruitment subunit in the E3 ubiquitin ligase complex and recruits hydroxylated hypoxia-inducible factor (HIF) under normoxic conditions. Involved in transcriptional repression through interaction with HIF1A, HIF1AN and histone deacetylases. Ubiquitinates, in an oxygen-responsive manner, ADRB2. Acts as a negative regulator of mTORC1 by promoting ubiquitination and degradation of RPTOR.

Subunit / interactions. Component of the VCB (VHL-Elongin BC-CUL2) complex; this complex acts as a ubiquitin-ligase E3 and directs proteasome-dependent degradation of targeted proteins. Interacts with CUL2; this interaction is dependent on the integrity of the trimeric VCB complex. Interacts (via the beta domain) with HIF1A (via the NTAD domain); this interaction mediates degradation of HIF1A in normoxia and, in hypoxia, prevents ubiquitination and degradation of HIF1A by mediating hypoxia-induced translocation to the nucleus, a process which requires a hypoxia-dependent regulatory signal. Interacts with ADRB2; the interaction, in normoxia, is dependent on hydroxylation of ADRB2 and the subsequent VCB-mediated ubiquitination and degradation of ADRB2. Under hypoxia, hydroxylation, interaction with VHL, ubiquitination and subsequent degradation of ADRB2 are dramatically decreased. Interacts with RNF139, USP33 and JADE1. Found in a complex composed of LIMD1, VHL, EGLN1/PHD2, ELOB and CUL2. Isoform 1 and isoform 3 interact with LIMD1 (via LIM zinc-binding 2), AJUBA (via LIM domains) and WTIP (via LIM domains). Interacts with EPAS1. Interacts with CARD9. Interacts with DCUN1D1 independently of CUL2; this interaction engages DCUN1D1 in the VCB complex and triggers CUL2 neddylation and consequently cullin ring ligase (CRL) substrates polyubiquitylation. Interacts with ALAS1 (hydroxylated form). Interacts with IGFBP1.

Subcellular location. Cytoplasm. Cell membrane. Endoplasmic reticulum. Nucleus Cytoplasm. Nucleus.

Tissue specificity. Expressed in the adult and fetal brain and kidney.

Disease relevance. Pheochromocytoma (PCC) [MIM:171300] A catecholamine-producing tumor of chromaffin tissue of the adrenal medulla or sympathetic paraganglia. The cardinal symptom, reflecting the increased secretion of epinephrine and norepinephrine, is hypertension, which may be persistent or intermittent. Disease susceptibility is associated with variants affecting the gene represented in this entry. von Hippel-Lindau disease (VHLD) [MIM:193300] VHLD is a dominantly inherited familial cancer syndrome predisposing to a variety of malignant and benign neoplasms, most frequently retinal, cerebellar and spinal hemangioblastoma, renal cell carcinoma (RCC), pheochromocytoma, and pancreatic tumors. VHL type 1 is without pheochromocytoma, type 2 is with pheochromocytoma. VHL type 2 is further subdivided into types 2A (pheochromocytoma, retinal angioma, and hemangioblastomas without renal cell carcinoma and pancreatic cyst) and 2B (pheochromocytoma, retinal angioma, and hemangioblastomas with renal cell carcinoma and pancreatic cyst). The disease is caused by variants affecting the gene represented in this entry. Erythrocytosis, familial, 2 (ECYT2) [MIM:263400] An autosomal recessive disorder characterized by an increase in serum red blood cell mass, hypersensitivity of erythroid progenitors to erythropoietin, increased erythropoietin serum levels, and normal oxygen affinity. Patients with ECYT2 carry a high risk for peripheral thrombosis and cerebrovascular events. The disease is caused by variants affecting the gene represented in this entry. Renal cell carcinoma (RCC) [MIM:144700] Renal cell carcinoma is a heterogeneous group of sporadic or hereditary carcinoma derived from cells of the proximal renal tubular epithelium. It is subclassified into clear cell renal carcinoma (non-papillary carcinoma), papillary renal cell carcinoma, chromophobe renal cell carcinoma, collecting duct carcinoma with medullary carcinoma of the kidney, and unclassified renal cell carcinoma. Clear cell renal cell carcinoma is the most common subtype. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The Elongin BC complex binding domain is also known as BC-box with the consensus [APST]-L-x(3)-C-x(3)-[AILV].

Pathway. Protein modification; protein ubiquitination.

Miscellaneous. Major isoform. Produced by alternative initiation at Met-54 of isoform 1.

Similarity. Belongs to the VHL family.

Isoforms (3)

UniProt ID	Names	Canonical?
P40337-1	1, VHL30, VHLp24(MPR)	yes
P40337-2	2
P40337-3	3, VHL19, VHLp18(MEA)

RefSeq proteins (3): NP_000542, NP_001341652, NP_937799 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR022772	VHL_tumour_suppress_b/a_dom	Domain
IPR024048	VHL_alpha_dom	Domain
IPR024053	VHL_beta_dom	Domain
IPR036208	VHL_sf	Homologous_superfamily
IPR037139	VHL_alpha_dom_sf	Homologous_superfamily
IPR037140	VHL_beta_dom_sf	Homologous_superfamily

Pfam: PF01847, PF17211

Enzyme classification (BRENDA):

• EC 2.3.2.B13 — (BRENDA: organisms, substrates, inhibitors, Km, kcat entries)

UniProt features (169 total): sequence variant 133, strand 12, repeat 8, helix 6, region of interest 4, splice variant 2, chain 1, compositionally biased region 1, mutagenesis site 1, turn 1

Structure

Experimental structures (PDB)

142 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
7Z76	X-RAY DIFFRACTION	1.32
9GIO	X-RAY DIFFRACTION	1.49
7JTO	X-RAY DIFFRACTION	1.7
8BDS	X-RAY DIFFRACTION	1.72
4AJY	X-RAY DIFFRACTION	1.73
6GMR	X-RAY DIFFRACTION	1.75
6HR2	X-RAY DIFFRACTION	1.76
6I7Q	X-RAY DIFFRACTION	1.8
8BB3	X-RAY DIFFRACTION	1.8
6GFX	X-RAY DIFFRACTION	1.83
1LM8	X-RAY DIFFRACTION	1.85
6ZHC	X-RAY DIFFRACTION	1.92
6GMN	X-RAY DIFFRACTION	1.94
6I7R	X-RAY DIFFRACTION	1.95
7Z77	X-RAY DIFFRACTION	1.97
8P0F	X-RAY DIFFRACTION	1.98
9BOL	X-RAY DIFFRACTION	1.99
1LQB	X-RAY DIFFRACTION	2
4B9K	X-RAY DIFFRACTION	2
6BVB	X-RAY DIFFRACTION	2
8BDJ	X-RAY DIFFRACTION	2.02
8BDM	X-RAY DIFFRACTION	2.02
8BB2	X-RAY DIFFRACTION	2.05
9EQJ	X-RAY DIFFRACTION	2.05
4W9F	X-RAY DIFFRACTION	2.1
4W9H	X-RAY DIFFRACTION	2.1
4W9K	X-RAY DIFFRACTION	2.1
5NVV	X-RAY DIFFRACTION	2.1
5NW1	X-RAY DIFFRACTION	2.1
8BDI	X-RAY DIFFRACTION	2.11

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P40337-F1	85.45	0.72

Functional residue map

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

Mutagenesis-validated functional residues (1):

Position	Phenotype
98	no interaction with hif1a. no hif1a degradation.

Function

Pathways and Gene Ontology

Reactome pathways

7 pathways

ID	Pathway
R-HSA-1234176	Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha
R-HSA-3232142	SUMOylation of ubiquitinylation proteins
R-HSA-8951664	Neddylation
R-HSA-9682706	Replication of the SARS-CoV-1 genome
R-HSA-9694686	Replication of the SARS-CoV-2 genome
R-HSA-9706019	RHOBTB3 ATPase cycle
R-HSA-983168	Antigen processing: Ubiquitination & Proteasome degradation

MSigDB gene sets: 432 (showing top): GSE45365_CTRL_VS_MCMV_INFECTION_NK_CELL_UP, GSE18804_SPLEEN_MACROPHAGE_VS_COLON_TUMORAL_MACROPHAGE_UP, GOBP_REGULATION_OF_AUTOPHAGY, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, REACTOME_CLASS_I_MHC_MEDIATED_ANTIGEN_PROCESSING_PRESENTATION, REACTOME_ANTIGEN_PROCESSING_UBIQUITINATION_PROTEASOME_DEGRADATION, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, DARWICHE_SKIN_TUMOR_PROMOTER_DN, DARWICHE_PAPILLOMA_RISK_LOW_DN, DARWICHE_PAPILLOMA_RISK_HIGH_UP, DARWICHE_SQUAMOUS_CELL_CARCINOMA_UP, GOBP_CELL_SURFACE_RECEPTOR_SIGNALING_PATHWAY_VIA_JAK_STAT, HERNANDEZ_ABERRANT_MITOSIS_BY_DOCETACEL_2NM_UP, GOBP_NEGATIVE_REGULATION_OF_INTRACELLULAR_SIGNAL_TRANSDUCTION, GOBP_NEGATIVE_REGULATION_OF_AUTOPHAGY

GO Biological Process (23): negative regulation of transcription by RNA polymerase II (GO:0000122), cell morphogenesis (GO:0000902), regulation of DNA-templated transcription (GO:0006355), proteolysis (GO:0006508), negative regulation of cell population proliferation (GO:0008285), negative regulation of signal transduction (GO:0009968), regulation of gene expression (GO:0010468), negative regulation of autophagy (GO:0010507), negative regulation of gene expression (GO:0010629), protein ubiquitination (GO:0016567), negative regulation of transcription elongation by RNA polymerase II (GO:0034244), negative regulation of apoptotic process (GO:0043066), proteasome-mediated ubiquitin-dependent protein catabolic process (GO:0043161), positive regulation of cell differentiation (GO:0045597), positive regulation of DNA-templated transcription (GO:0045893), negative regulation of receptor signaling pathway via JAK-STAT (GO:0046426), protein stabilization (GO:0050821), cellular response to hypoxia (GO:0071456), regulation of cellular response to hypoxia (GO:1900037), negative regulation of TORC1 signaling (GO:1904262), amyloid fibril formation (GO:1990000), response to hypoxia (GO:0001666), negative regulation of macromolecule biosynthetic process (GO:0010558)

GO Molecular Function (9): transcription elongation factor activity (GO:0003711), transcription corepressor activity (GO:0003714), ubiquitin-protein transferase activity (GO:0004842), enzyme binding (GO:0019899), molecular adaptor activity (GO:0060090), protein serine/threonine kinase binding (GO:0120283), DNA-binding transcription factor binding (GO:0140297), ubiquitin-like ligase-substrate adaptor activity (GO:1990756), protein binding (GO:0005515)

GO Cellular Component (11): nucleus (GO:0005634), nucleoplasm (GO:0005654), mitochondrion (GO:0005739), endoplasmic reticulum (GO:0005783), cytosol (GO:0005829), plasma membrane (GO:0005886), cilium (GO:0005929), microtubule cytoskeleton (GO:0015630), ciliary tip (GO:0097542), cytoplasm (GO:0005737), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-7 pathways:

Category	Pathways
Cellular response to hypoxia	1
SUMO E3 ligases SUMOylate target proteins	1
Post-translational protein modification	1
SARS-CoV-1 Genome Replication and Transcription	1
SARS-CoV-2 Genome Replication and Transcription	1
Signaling by Rho GTPases, Miro GTPases and RHOBTB3	1
Class I MHC mediated antigen processing & presentation	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	5
intracellular membrane-bounded organelle	3
cytoplasm	3
negative regulation of DNA-templated transcription	2
DNA-templated transcription	2
regulation of gene expression	2
gene expression	2
binding	2
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
anatomical structure morphogenesis	1
regulation of RNA biosynthetic process	1
protein metabolic process	1
cell population proliferation	1
regulation of cell population proliferation	1
negative regulation of cellular process	1
signal transduction	1
regulation of signal transduction	1
negative regulation of cell communication	1
negative regulation of signaling	1
negative regulation of response to stimulus	1
regulation of macromolecule biosynthetic process	1
autophagy	1
negative regulation of catabolic process	1
regulation of autophagy	1
negative regulation of macromolecule biosynthetic process	1
protein modification by small protein conjugation	1
transcription elongation by RNA polymerase II	1
negative regulation of DNA-templated transcription, elongation	1
regulation of transcription elongation by RNA polymerase II	1
apoptotic process	1
regulation of apoptotic process	1
negative regulation of programmed cell death	1
ubiquitin-dependent protein catabolic process	1
proteasomal protein catabolic process	1
cell differentiation	1
regulation of cell differentiation	1
positive regulation of cellular process	1
positive regulation of developmental process	1
regulation of DNA-templated transcription	1

Protein interactions and networks

STRING

1785 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
VHL	ELOC	Q15369	999
VHL	CUL2	Q13617	998
VHL	HIF1A	Q16665	998
VHL	ELOB	Q15370	997
VHL	RBX1	P62877	995
VHL	EPAS1	Q99814	967
VHL	EGLN1	Q9GZT9	950
VHL	USP1	O94782	920
VHL	USP33	Q8TEY7	919
VHL	ARNT	P27540	901
VHL	EGLN2	Q96KS0	871
VHL	EGLN3	Q9H6Z9	870
VHL	SLC49A4	Q96SL1	817
VHL	TCHP	Q9BT92	813
VHL	VBP1	P61758	809

IntAct

407 interactions, top by confidence:

A	B	Type	Score
VHL	MDFI	psi-mi:“MI:0915”(physical association)	0.670
MDFI	VHL	psi-mi:“MI:0915”(physical association)	0.670
TCP1	VHL	psi-mi:“MI:0407”(direct interaction)	0.440
JADE1	VHL	psi-mi:“MI:0915”(physical association)	0.370
VHL	CUL2	psi-mi:“MI:0915”(physical association)	0.000
VHL	ELOB	psi-mi:“MI:0915”(physical association)	0.000
VHL	NEDD8	psi-mi:“MI:0915”(physical association)	0.000
VHL	ELOC	psi-mi:“MI:0915”(physical association)	0.000
VHL	RPA3	psi-mi:“MI:0915”(physical association)	0.000
VHL	RBX1	psi-mi:“MI:0915”(physical association)	0.000
VHL	RHPN2	psi-mi:“MI:0915”(physical association)	0.000
VHL	FKBP1A	psi-mi:“MI:0915”(physical association)	0.000
VHL	ATIC	psi-mi:“MI:0915”(physical association)	0.000
VHL	UBE2N	psi-mi:“MI:0915”(physical association)	0.000
VHL		psi-mi:“MI:0915”(physical association)	0.000
VHL	RPL22	psi-mi:“MI:0915”(physical association)	0.000
VHL	PSMA2	psi-mi:“MI:0915”(physical association)	0.000
VHL	ACLY	psi-mi:“MI:0915”(physical association)	0.000
VHL	RAB7A	psi-mi:“MI:0915”(physical association)	0.000
VHL	RAB1B	psi-mi:“MI:0915”(physical association)	0.000
VHL	PFN2	psi-mi:“MI:0915”(physical association)	0.000
VHL	PCMT1	psi-mi:“MI:0915”(physical association)	0.000
VHL	KNTC1	psi-mi:“MI:0915”(physical association)	0.000
VHL	ANXA2	psi-mi:“MI:0915”(physical association)	0.000
VHL	TAGLN2	psi-mi:“MI:0915”(physical association)	0.000
VHL	EZR	psi-mi:“MI:0915”(physical association)	0.000
VHL	RPL37A	psi-mi:“MI:0915”(physical association)	0.000
VHL	LRRC59	psi-mi:“MI:0915”(physical association)	0.000
VHL	SET	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (1330): USP33 (Biochemical Activity), VHL (Co-crystal Structure), TPT1 (Reconstituted Complex), TPT1 (Affinity Capture-Western), VHL (Affinity Capture-Western), VHL (Affinity Capture-Western), VHL (Two-hybrid), PLD1 (Affinity Capture-Western), PLD1 (Reconstituted Complex), VHL (Reconstituted Complex), HIF1A (Affinity Capture-Western), VHL (Co-localization), UBC (Reconstituted Complex), UBE2D2 (Reconstituted Complex), VHL (Affinity Capture-MS)

ESM2 similar proteins: A2RRU4, A4D1U4, A6QM06, B0KWQ2, D3YYI7, D4ABP9, G3X9C2, P29590, P30291, P40337, P40338, P97260, Q08E57, Q0PGW2, Q0VCT3, Q12770, Q2TBA3, Q3UHG7, Q3UI43, Q496Y0, Q4R4I0, Q5BK68, Q5EBM0, Q5GH73, Q5MNU5, Q5Q9Z2, Q5R7L2, Q5RF77, Q5XIJ6, Q64259, Q6DVA0, Q6GQT6, Q6L9W6, Q6NS60, Q80Z30, Q8HXH0, Q8K2I9, Q8NC56, Q8NFZ0, Q8TC41

Diamond homologs: P40337, P40338, Q5Q9Z2, Q64259, Q6RSH7, Q9V3C1

SIGNOR signaling

16 interactions.

A	Effect	B	Mechanism
CHEK2	up-regulates	VHL	phosphorylation
VHL	“down-regulates quantity by repression”	KLF10	“transcriptional regulation”
VHL	“up-regulates quantity by expression”	CDKN1C	“transcriptional regulation”
VHL	“up-regulates quantity by expression”	DAB2	“transcriptional regulation”
VHL	“up-regulates quantity by expression”	SPARC	“transcriptional regulation”
VHL	“up-regulates quantity by stabilization”	TP53	binding
VHL	“down-regulates activity”	CARD9	binding
VHL	“down-regulates quantity by destabilization”	IREB2	ubiquitination
VHL	“form complex”	VCB-Cul2	binding
NEK1	“down-regulates quantity by destabilization”	VHL	phosphorylation
CDK1	“down-regulates quantity by destabilization”	VHL	phosphorylation
SRC	“down-regulates quantity by destabilization”	VHL	phosphorylation
AURKA	“down-regulates quantity by destabilization”	VHL	phosphorylation
CDK1	“up-regulates activity”	VHL	phosphorylation
VHL	down-regulates	“HIF-1 complex”	ubiquitination

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 179 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
Antigen processing: Ub, ATP-independent proteasomal degradation	5	18.9×	1e-04
Vif-mediated degradation of APOBEC3G	9	15.1×	8e-07
Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha	11	14.3×	5e-08
Interleukin-12 signaling	5	13.5×	4e-04
Orc1 removal from chromatin	10	11.8×	1e-06
FBXL7 down-regulates AURKA during mitotic entry and in early mitosis	7	11.5×	7e-05
GSK3B and BTRC:CUL1-mediated-degradation of NFE2L2	7	11.5×	7e-05
Ribosome Quality Control (RQC) complex extracts and degrades nascent peptide	16	11.3×	2e-10

GO biological processes:

GO term	Partners	Fold	FDR
cytoplasmic translation	10	10.6×	4e-05
protein folding	11	6.5×	5e-04
translation	11	6.5×	5e-04

Disease & clinical

Cancer significance

From CIViC — curated cancer-variant interpretation:

Von Hippel-Lindau (VHL) disease is characterized by heterozygous germline mutation in VHL gene on chromosome 3p. Patients are predisposed to developing hemangioblastomas of the brain, spinal cord, and retina; renal cysts and clear cell renal cell carcinoma; pheochromocytoma, pancreatic cysts and neuroendocrine tumors; endolymphatic sac tumors; and epididymal and broad ligament cysts. Cerebellar hemangioblastomas may be associated with headache, vomiting, gait disturbances, or ataxia. Spinal hemangioblastomas and related syrinx usually present with pain. Sensory and motor loss may develop with cord compression. Retinal hemangioblastomas may be the initial manifestation of VHL disease and can cause vision loss. Renal cell carcinoma occurs in about 70% of individuals with VHL and is the leading cause of mortality. Pheochromocytomas can be asymptomatic but may cause sustained or episodic hypertension. Pancreatic lesions often remain asymptomatic and rarely cause endocrine or exocrine insufficiency. Endolymphatic sac tumors can cause hearing loss of varying severity, which can be a presenting symptom. Cystadenomas of the epididymis are relatively common. They rarely cause problems, unless bilateral, in which case they may result in infertility. The VHL gene product encodes pVHL, which binds to elongin C, elongin B, cullin-2 and Rbx1. This complex catalyzes the polyubiquitinylation of specific proteins and targets them for degradation by proteosomes. For example, under normoxic conditions, hydroxylated hypoxia-inducble factor alpha subunits (HIFα) binds pVHL targets HIFα for degradation. Under hypoxic conditions, HIF1α is not hydroxylated, pVHL does not bind, and HIF1α subunits accumulate. HIF1α forms heterodimers with HIF1β and activates transcription of a variety of hypoxia-inducible genes (i.e., VEGF, EPO, TGFα, PDGFβ). Likewise, when pVHL is absent or mutated, HIF1α subunits accumulate, resulting in cell proliferation and the neovascularization of tumors characteristic of VHL disease. Pathogenic variants in VHL either prevent its expression (i.e., deletions, frameshifts, nonsense mutations, and splice site mutations) or lead to the expression of an abnormal protein (i.e., missense mutations). Missense mutations that destabilize packing of the alpha-helical domains, decrease the stability of the alpha-beta domain interface, interfere with binding of elongin C and HIF1α, or disrupt hydrophobic core residues result in loss of HIF regulation and are more likely to result in VHL type 1 (no predisposition to pheochromocytoma). Missense mutations that result in pVHL that is normal with respect to HIF regulation are more likely to be associated with VHL with clinical pheochromocytoma. Acquired somatic pathogenic variants in VHL may give rise to sporadic VHL-type tumors (i.e., clear cell RCC and hemangioblastoma) without other associated tumors characteristic of the hereditary disease. It should be noted that >90% of the most common form of kidney cancer (clear cell renal cell carcinoma) are associated with bi-allelic somatic mutation in the VHL gene, and is the rationale for the anti-angiogenic therapy for RCC patients.

From intOGen — cancer-driver classification: loss-of-function (tumor-suppressor-like) across 3 cancer types — CCRCC, PGNG, RCC.

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	136
Likely pathogenic	40
Uncertain significance	414
Likely benign	128
Benign	25

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1071196	NM_000551.4(VHL):c.244_259dup (p.Val87fs)	Pathogenic
1072069	NM_000551.4(VHL):c.241_244dup (p.Arg82fs)	Pathogenic
1073436	NC_000003.11:g.(?10183532)(10188330_?)del	Pathogenic
1076108	NM_000551.4(VHL):c.298del (p.Thr100fs)	Pathogenic
1297059	NM_000551.4(VHL):c.244C>G (p.Arg82Gly)	Pathogenic
1426858	NM_000551.4(VHL):c.193T>A (p.Ser65Thr)	Pathogenic
1448469	NM_000551.4(VHL):c.314dup (p.Arg107fs)	Pathogenic
1452589	NC_000003.11:g.(?10183579)(10185909_?)del	Pathogenic
1743417	NM_000551.4(VHL):c.482G>C (p.Arg161Pro)	Pathogenic
1746298	NM_000551.4(VHL):c.524_527del (p.Asn174_Tyr175insTer)	Pathogenic
1780385	NM_000551.4(VHL):c.180_193del (p.Pro61fs)	Pathogenic
1782641	NM_000551.4(VHL):c.191dup (p.Ser65fs)	Pathogenic
1785035	NM_000551.4(VHL):c.204dup (p.Arg69fs)	Pathogenic
1785370	NM_000551.4(VHL):c.207_208dup (p.Glu70fs)	Pathogenic
1786236	NM_000551.4(VHL):c.212_213dup (p.Ser72fs)	Pathogenic
1792371	NM_000551.4(VHL):c.250del (p.Val84fs)	Pathogenic
1793789	NM_000551.4(VHL):c.261_262dup (p.Trp88fs)	Pathogenic
182975	NM_000551.4(VHL):c.194C>T (p.Ser65Leu)	Pathogenic
182977	NM_000551.4(VHL):c.257C>T (p.Pro86Leu)	Pathogenic
182978	NM_000551.4(VHL):c.263G>A (p.Trp88Ter)	Pathogenic
182986	NM_000551.4(VHL):c.180del (p.Val62fs)	Pathogenic
182988	NM_000551.4(VHL):c.219_220del (p.Gln73fs)	Pathogenic
193118	NM_000551.4(VHL):c.245G>C (p.Arg82Pro)	Pathogenic
1999272	NM_000551.4(VHL):c.329dup (p.His110fs)	Pathogenic
2028206	NM_000551.4(VHL):c.231C>A (p.Cys77Ter)	Pathogenic
2085211	NM_000551.4(VHL):c.184del (p.Val62fs)	Pathogenic
2128789	NM_000551.4(VHL):c.189_193dup (p.Ser65fs)	Pathogenic
2203305	NM_000551.4(VHL):c.330_331delinsTT (p.Ser111Cys)	Pathogenic
220414	NM_000551.4(VHL):c.337C>T (p.Arg113Ter)	Pathogenic
220487	NM_000551.4(VHL):c.258del (p.Val87fs)	Pathogenic

SpliceAI

364 predictions. Top by Δscore:

Variant	Effect	Δscore
3:10149782:TCCA:T	acceptor_loss	1.0000
3:10149783:CCA:C	acceptor_loss	1.0000
3:10149785:A:AG	acceptor_gain	1.0000
3:10149785:AGT:A	acceptor_gain	1.0000
3:10149786:G:GA	acceptor_gain	1.0000
3:10149786:GT:G	acceptor_gain	1.0000
3:10149786:GTG:G	acceptor_gain	1.0000
3:10149786:GTGT:G	acceptor_gain	1.0000
3:10149786:GTGTA:G	acceptor_gain	0.9900
3:10142188:GT:G	donor_loss	0.9800
3:10146632:GCCAG:G	donor_loss	0.9600
3:10146633:CCAG:C	donor_loss	0.9600
3:10146635:AG:A	donor_loss	0.9600
3:10146636:G:GC	donor_loss	0.9600
3:10146637:GTACT:G	donor_loss	0.9600
3:10146638:T:C	donor_loss	0.9600
3:10142185:GAG:G	donor_gain	0.9500
3:10146503:T:A	acceptor_loss	0.9300
3:10146508:CGATA:C	acceptor_loss	0.9300
3:10146509:GATAG:G	acceptor_loss	0.9300
3:10146510:ATAG:A	acceptor_loss	0.9300
3:10146511:T:TG	acceptor_loss	0.9300
3:10146512:A:AC	acceptor_loss	0.9300
3:10146513:GG:G	acceptor_loss	0.9300
3:10142188:G:GG	donor_gain	0.9200
3:10146504:GTCCC:G	acceptor_loss	0.9200
3:10149791:T:G	acceptor_gain	0.8900
3:10149776:T:TA	acceptor_gain	0.8800
3:10142235:TCTG:T	donor_gain	0.8700
3:10149787:T:TA	acceptor_gain	0.8500

AlphaMissense

1370 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:10142074:T:C	F76S	0.999
3:10142081:T:A	N78K	0.999
3:10142081:T:G	N78K	0.999
3:10142085:A:C	S80R	0.999
3:10142087:T:A	S80R	0.999
3:10142087:T:G	S80R	0.999
3:10142109:T:A	W88R	0.999
3:10142109:T:C	W88R	0.999
3:10142178:A:C	S111R	0.999
3:10142180:C:A	S111R	0.999
3:10142180:C:G	S111R	0.999
3:10146522:T:A	W117R	0.999
3:10146522:T:C	W117R	0.999
3:10146528:T:C	F119L	0.999
3:10146530:C:A	F119L	0.999
3:10146530:C:G	F119L	0.999
3:10142079:A:G	N78D	0.998
3:10142118:T:C	F91L	0.998
3:10142120:C:A	F91L	0.998
3:10142120:C:G	F91L	0.998
3:10142125:G:T	G93V	0.998
3:10146523:G:C	W117S	0.998
3:10146524:G:C	W117C	0.998
3:10146524:G:T	W117C	0.998
3:10146529:T:C	F119S	0.998
3:10146619:C:A	A149D	0.998
3:10146625:T:A	I151N	0.998
3:10149807:T:C	C162R	0.998
3:10149809:C:G	C162W	0.998
3:10142104:C:A	P86H	0.997

dbSNP variants (sampled 300 via entrez): RS1000003242 (3:10149520 C>G), RS1000010795 (3:10142441 G>A,C), RS1000074994 (3:10148022 G>A,C), RS1001312741 (3:10144395 G>A), RS1002154843 (3:10145489 A>G), RS1002251146 (3:10145784 T>G), RS1002334185 (3:10150552 G>A,C,T), RS1002503418 (3:10151309 A>G), RS1002553876 (3:10144616 T>A), RS1002585215 (3:10144245 T>C), RS1002624853 (3:10150328 T>C), RS1002644446 (3:10151549 AG>A), RS1002870918 (3:10140751 T>C), RS1002902052 (3:10141166 T>G), RS1003364563 (3:10146641 T>A,C,G)

Disease associations

OMIM: gene MIM:608537 | disease phenotypes: MIM:193300, MIM:263400, MIM:144700, MIM:171300, MIM:167000, MIM:166000, MIM:613254, MIM:614569

GenCC curated gene-disease

Disease	Classification	Inheritance
von Hippel-Lindau disease	Definitive	Autosomal dominant
pheochromocytoma	Definitive	Autosomal dominant
autosomal recessive secondary polycythemia not associated with VHL gene	Strong	Autosomal recessive
renal cell carcinoma	Strong	Autosomal dominant
Chuvash polycythemia	Strong	Autosomal recessive
hereditary pheochromocytoma-paraganglioma	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
von Hippel-Lindau disease	Definitive	AD

Mondo (17): von Hippel-Lindau disease (MONDO:0008667), Chuvash polycythemia (MONDO:0009892), hereditary neoplastic syndrome (MONDO:0015356), nonpapillary renal cell carcinoma (MONDO:0007763), pheochromocytoma (MONDO:0008233), ovarian cancer (MONDO:0008170), polycythemia (MONDO:0005571), Ollier disease (MONDO:0008145), hepatoblastoma (MONDO:0018666), retinal hemangioblastoma (MONDO:0003343), cerebellar hemangioblastoma (MONDO:0003901), diffuse midline glioma, H3 K27-altered (MONDO:1060171), tuberous sclerosis 2 (MONDO:0013199), Maffucci syndrome (MONDO:0013808), autosomal recessive secondary polycythemia not associated with VHL gene (MONDO:0016598)

Orphanet (11): Inherited cancer-predisposing syndrome (Orphanet:140162), Chuvash erythrocytosis (Orphanet:238557), Von Hippel-Lindau disease (Orphanet:892), Hereditary pheochromocytoma-paraganglioma (Orphanet:29072), Hereditary clear cell renal cell carcinoma (Orphanet:422526), Rare ovarian cancer (Orphanet:213500), Polycythemia (Orphanet:98427), Ollier disease (Orphanet:296), Hepatoblastoma (Orphanet:449), Tuberous sclerosis complex (Orphanet:805), Maffucci syndrome (Orphanet:163634)

HPO phenotypes

105 total (30 of 105 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000093	Proteinuria
HP:0000096	Glomerular sclerosis
HP:0000360	Tinnitus
HP:0000405	Conductive hearing impairment
HP:0000407	Sensorineural hearing impairment
HP:0000478	Abnormality of the eye
HP:0000519	Developmental cataract
HP:0000526	Aniridia
HP:0000541	Retinal detachment
HP:0000572	Visual loss
HP:0000739	Anxiety
HP:0000740	Episodic paroxysmal anxiety
HP:0000790	Hematuria
HP:0000822	Hypertension
HP:0000875	Episodic hypertension
HP:0000957	Cafe-au-lait spot
HP:0000975	Hyperhidrosis
HP:0000980	Pallor
HP:0001028	Hemangioma
HP:0001050	Plethora
HP:0001069	Episodic hyperhidrosis
HP:0001085	Papilledema
HP:0001095	Hypertensive retinopathy
HP:0001293	Cranial nerve compression
HP:0001297	Stroke
HP:0001337	Tremor
HP:0001342	Cerebral hemorrhage
HP:0001508	Failure to thrive

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST011940_2	Bullous pemphigoid	9.000000e-38
GCST90020028_767	Hip circumference adjusted for BMI	2.000000e-08

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0008039	BMI-adjusted hip circumference

MeSH disease descriptors (9)

Descriptor	Name	Tree numbers
D002292	Carcinoma, Renal Cell	C04.557.470.200.025.390; C04.588.945.947.535.160; C12.050.351.937.820.535.160; C12.050.351.968.419.473.160; C12.200.758.820.750.160; C12.200.777.419.473.160; C12.900.820.535.160; C12.950.419.473.160; C12.950.983.535.160
D018197	Hepatoblastoma	C04.557.435.380
D009386	Neoplastic Syndromes, Hereditary	C04.700; C16.320.700
D010051	Ovarian Neoplasms	C04.588.322.455; C12.050.351.500.056.630.705; C12.050.351.937.418.685; C12.100.250.056.630.705; C12.900.418.685; C19.344.410; C19.391.630.705
D010673	Pheochromocytoma	C04.557.465.625.650.700.725; C04.557.580.625.650.700.725
D011086	Polycythemia	C15.378.738
D006623	von Hippel-Lindau Disease	C10.562.925; C14.907.077.925; C16.131.077.245.750; C16.320.184.750
C563918	Erythrocytosis, Familial, 2 (supp.)
C566021	Tuberous Sclerosis 2 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (205): CHEMBL3108660 (SINGLE PROTEIN), CHEMBL3301400 (PROTEIN COMPLEX), CHEMBL4296117 (PROTEIN COMPLEX), CHEMBL4296139 (PROTEIN-PROTEIN INTERACTION), CHEMBL4296140 (PROTEIN-PROTEIN INTERACTION), CHEMBL4296141 (PROTEIN-PROTEIN INTERACTION), CHEMBL4296142 (PROTEIN-PROTEIN INTERACTION), CHEMBL4296143 (PROTEIN-PROTEIN INTERACTION), CHEMBL4296144 (PROTEIN-PROTEIN INTERACTION), CHEMBL4296146 (PROTEIN-PROTEIN INTERACTION)

Molecules with ChEMBL bioactivity

7 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 35,478 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL3353410	OSIMERTINIB	4	8,898
CHEMBL3545311	BRIGATINIB	4	5,634
CHEMBL601719	CRIZOTINIB	4	14,403
CHEMBL4594350	ADAGRASIB	4	2,814
CHEMBL4081711	ZIMLOVISERTIB	2	522
CHEMBL1230609	FORETINIB	2	3,096
CHEMBL4745523	DT-2216	1	111

Clinical evidence (CIViC)

Drug × variant × indication: 8 predictive associations from 8 curated evidence items; also 1557 predisposing, 25 oncogenic, 4 functional, 3 prognostic, 3 diagnostic.

Variant	Therapy	Indication	Effect	Level	CIViC
VHL Mutation	Pazopanib	Renal Cell Carcinoma	Sensitivity/Response	CIViC B	EID1672
VHL Mutation	Anti-VEGF Monoclonal Antibody	Renal Cell Carcinoma	Sensitivity/Response	CIViC B	EID4832
VHL Mutation	Everolimus	Renal Cell Carcinoma	Sensitivity/Response	CIViC B	EID5323
VHL Loss	Pazopanib	Renal Cell Carcinoma	Resistance	CIViC B	EID4829
VHL N78S (c.233A>G)	Sunitinib	Von Hippel-Lindau Disease	Sensitivity/Response	CIViC C	EID6429
VHL R200W (c.598C>T)	Ruxolitinib	Chuvash Polycythemia	Sensitivity/Response	CIViC C	EID1608
VHL Loss	Temsirolimus	Renal Carcinoma	Sensitivity/Response	CIViC D	EID1035
VHL Loss-of-function	Temsirolimus	Renal Cell Carcinoma	Sensitivity/Response	CIViC D	EID4828

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
MS8815	Binding	6.7	pKd

Binding affinities (BindingDB)

16 measured of 17 human assays (17 total across all organisms); most potent 16 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
5-[2-(4-methyl-2-pyridinyl)-3-oxo-1H-pyrazol-4-yl]pyridine-2-carbonitrile	IC50	180 nM	US-9085572: 4-(pyridin-3-yl)-2(pyridin-2yl)-1,2-dihydro-3H-pyrazol-3-one derivatives as specific HIF-pyrolyl-4-hydroxylase inhibitors for treating cardiovascular and haematological diseases
2-pyridin-2-yl-4-pyridin-3-yl-1H-pyrazol-3-one	IC50	430 nM	US-9085572: 4-(pyridin-3-yl)-2(pyridin-2yl)-1,2-dihydro-3H-pyrazol-3-one derivatives as specific HIF-pyrolyl-4-hydroxylase inhibitors for treating cardiovascular and haematological diseases
N-[[2-(3-oxo-4-pyridin-3-yl-1H-pyrazol-2-yl)-4-pyridinyl]methyl]-2-phenylacetamide	IC50	700 nM	US-9085572: 4-(pyridin-3-yl)-2(pyridin-2yl)-1,2-dihydro-3H-pyrazol-3-one derivatives as specific HIF-pyrolyl-4-hydroxylase inhibitors for treating cardiovascular and haematological diseases
4-(2-methyl-3-pyridinyl)-2-pyridin-2-yl-1H-pyrazol-3-one	IC50	760 nM	US-9085572: 4-(pyridin-3-yl)-2(pyridin-2yl)-1,2-dihydro-3H-pyrazol-3-one derivatives as specific HIF-pyrolyl-4-hydroxylase inhibitors for treating cardiovascular and haematological diseases
8-(3,5-difluoro-2-pyridinyl)-N-[5-[[5-[(2S)-1-[(2R,4R)-4-hydroxy-2-[4-methyl-4-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]-5-oxo-1H-imidazol-2-yl]pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl]-1,2-oxazol-3-yl]oxy]pentyl]-15-methyl-4-(methylsulfonylmethyl)-14-oxo-8,12,15-triazatetracyclo[8.6.1.02,7.013,17]heptadeca-1(16),2(7),3,5,10,13(17)-hexaene-5-carboxamide	IC50	795 nM	US-11242344: (4-hydroxypyrrolidin-2-yl)-heterocyclic compounds and methods of use thereof
2-[5-(hydroxymethyl)-2-pyridinyl]-4-pyridin-3-yl-1H-pyrazol-3-one	IC50	860 nM	US-9085572: 4-(pyridin-3-yl)-2(pyridin-2yl)-1,2-dihydro-3H-pyrazol-3-one derivatives as specific HIF-pyrolyl-4-hydroxylase inhibitors for treating cardiovascular and haematological diseases
2-[4-(hydroxymethyl)-2-pyridinyl]-4-pyridin-3-yl-1H-pyrazol-3-one	IC50	1500 nM	US-9085572: 4-(pyridin-3-yl)-2(pyridin-2yl)-1,2-dihydro-3H-pyrazol-3-one derivatives as specific HIF-pyrolyl-4-hydroxylase inhibitors for treating cardiovascular and haematological diseases
N-[[2-(3-oxo-4-pyridin-3-yl-1H-pyrazol-2-yl)-4-pyridinyl]methyl]benzamide	IC50	1900 nM	US-9085572: 4-(pyridin-3-yl)-2(pyridin-2yl)-1,2-dihydro-3H-pyrazol-3-one derivatives as specific HIF-pyrolyl-4-hydroxylase inhibitors for treating cardiovascular and haematological diseases
3-(4-chloropyrazol-1-yl)-N-[[2-(3-oxo-4-pyridin-3-yl-1H-pyrazol-2-yl)-4-pyridinyl]methyl]propanamide	IC50	1900 nM	US-9085572: 4-(pyridin-3-yl)-2(pyridin-2yl)-1,2-dihydro-3H-pyrazol-3-one derivatives as specific HIF-pyrolyl-4-hydroxylase inhibitors for treating cardiovascular and haematological diseases
N-[[2-(3-oxo-4-pyridin-3-yl-1H-pyrazol-2-yl)-4-pyridinyl]methyl]acetamide	IC50	2200 nM	US-9085572: 4-(pyridin-3-yl)-2(pyridin-2yl)-1,2-dihydro-3H-pyrazol-3-one derivatives as specific HIF-pyrolyl-4-hydroxylase inhibitors for treating cardiovascular and haematological diseases
2-[4-(aminomethyl)-2-pyridinyl]-4-pyridin-3-yl-1H-pyrazol-3-one	IC50	2300 nM	US-9085572: 4-(pyridin-3-yl)-2(pyridin-2yl)-1,2-dihydro-3H-pyrazol-3-one derivatives as specific HIF-pyrolyl-4-hydroxylase inhibitors for treating cardiovascular and haematological diseases
(2S,4R)-4-hydroxy-N-methyl-1-[(2S)-3-methyl-2-[4-(1H-pyrrol-2-yl)triazol-1-yl]butanoyl]pyrrolidine-2-carboxamide	IC50	2650 nM	WO-2022104345: 1-(2-(4-CYCLOPROPYL-1H-1,2,3-TRIAZOL-1-YL)ACETYL)-4-HYDROXYPYRROLIDINE-2-CARBOXA|MIDE DERIVATIVES AS VHL INHIBITORS FOR THE TREATMENT OF ANEMIA
(2S,4R)-4-hydroxy-1-[(2S)-3-methyl-2-(3-oxo-1H-isoindol-2-yl)butanoyl]-N-[(4-pyrazolidin-3-ylphenyl)methyl]pyrrolidine-2-carboxamide	IC50	7280 nM	US-10730870: Compounds and methods for the enhanced degradation of targeted proteins
(2S,4R)-4-hydroxy-1-[(2S)-3-methyl-2-(3-oxo-1H-isoindol-2-yl)butanoyl]-N-[[4-(triazolidin-4-yl)phenyl]methyl]pyrrolidine-2-carboxamide	IC50	9770 nM	US-10730870: Compounds and methods for the enhanced degradation of targeted proteins
8-(3,5-difluoro-2-pyridinyl)-N-[5-[[5-[(2R)-1-[(4R)-4-hydroxy-2-[(4S)-4-methyl-4-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]-5-oxo-1H-imidazol-2-yl]pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl]-1,2-oxazol-3-yl]oxy]pentyl]-15-methyl-4-(methylsulfonylmethyl)-14-oxo-8,12,15-triazatetracyclo[8.6.1.02,7.013,17]heptadeca-1(16),2(7),3,5,10,13(17)-hexaene-5-carboxamide	IC50	16900 nM	US-11242344: (4-hydroxypyrrolidin-2-yl)-heterocyclic compounds and methods of use thereof
4-(3,5-difluoropyridin-2-yl)-N-(11-(((2S)-1-((4R)-4-hydroxy-2-((S)-5-methyl-5-(4-(4-methylthiazol-5-yl)phenyl)-4-oxo-4,5-dihydro-1H-imidazol-2-yl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-11-oxoundecyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-6-carboxamide (2 Single Diastereomers)	IC50	255000 nM	US-11242344: (4-hydroxypyrrolidin-2-yl)-heterocyclic compounds and methods of use thereof

ChEMBL bioactivities

966 potent at pChembl≥5 of 1240 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
10.06	Kd	0.088	nM	CHEMBL4746371
9.82	EC50	0.15	nM	CHEMBL5436180
9.68	Kd	0.21	nM	CHEMBL4761731
9.55	Kd	0.28	nM	CHEMBL4746371
9.52	IC50	0.3	nM	CHEMBL4476831
9.52	IC50	0.3	nM	CHEMBL4577622
9.52	Kd	0.3	nM	CHEMBL4796635
9.44	Kd	0.36	nM	CHEMBL4761731
9.40	IC50	0.4	nM	CHEMBL4581069
9.33	Kd	0.47	nM	CHEMBL4544893
9.27	Kd	0.54	nM	CHEMBL5532464
9.24	Kd	0.57	nM	CHEMBL4796635
9.22	IC50	0.6	nM	CHEMBL4578800
9.20	EC50	0.63	nM	CHEMBL5434442
9.17	Kd	0.67	nM	CHEMBL4797656
9.15	EC50	0.7	nM	CHEMBL5266174
9.12	EC50	0.76	nM	CHEMBL4740749
9.10	IC50	0.8	nM	CHEMBL4444805
9.07	EC50	0.86	nM	CHEMBL4740749
9.04	Kd	0.92	nM	CHEMBL4544893
9.00	IC50	1	nM	OSIMERTINIB
9.00	EC50	1	nM	CHEMBL5415117
9.00	EC50	1	nM	CHEMBL5394447
9.00	EC50	1	nM	CHEMBL5429484
8.96	EC50	1.1	nM	CHEMBL5266174
8.96	EC50	1.1	nM	CHEMBL5282858
8.89	Kd	1.3	nM	CHEMBL4797656
8.89	Kd	1.3	nM	CHEMBL6164855
8.85	IC50	1.4	nM	CHEMBL4205154
8.85	Kd	1.4	nM	CHEMBL6145694
8.82	IC50	1.5	nM	CHEMBL6120383
8.80	EC50	1.6	nM	CHEMBL5208515
8.77	EC50	1.7	nM	CHEMBL5208515
8.75	EC50	1.76	nM	CHEMBL5182441
8.70	EC50	2	nM	CHEMBL5208515
8.70	EC50	2	nM	CHEMBL5182441
8.70	EC50	2	nM	CHEMBL5412806
8.70	IC50	1.995	nM	CHEMBL5632137
8.68	IC50	2.1	nM	CHEMBL6149323
8.67	IC50	2.118	nM	CHEMBL5275081
8.66	Kd	2.2	nM	CHEMBL6168258
8.60	Kd	2.5	nM	CHEMBL4215078
8.55	Kd	2.8	nM	CHEMBL5568085
8.52	Kd	3	nM	CHEMBL5074720
8.52	EC50	3	nM	CHEMBL4447794
8.52	EC50	3	nM	CHEMBL5172806
8.52	IC50	3	nM	OSIMERTINIB
8.52	EC50	3	nM	CHEMBL5412232
8.52	EC50	3	nM	CHEMBL5402199
8.48	EC50	3.3	nM	CHEMBL5278697

PubChem BioAssay actives

603 with measured affinity, of 6100 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
N-(2-chloro-6-methylphenyl)-2-[[6-[4-[6-[2-[2-[2-[2-[2-[2-[[(2S)-1-[(2S,4R)-4-hydroxy-2-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methylcarbamoyl]pyrrolidin-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]amino]-2-oxoethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]hexyl]piperazin-1-yl]-2-methylpyrimidin-4-yl]amino]-1,3-thiazole-5-carboxamide	1678553: Protac binding affinity at VHL/BCR-ABL (unknown origin) assessed as binding to phosphorylated c-ABL kinase domain by Kinomescan assay	kd	0.0001	uM
N-[3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]-4-[4-[4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]piperazin-1-yl]piperidin-1-yl]benzamide	1784623: Protac activity at VHL/AR in human VCaP cells assessed as induction of AR degradation measured after 24 hrs by western blot analysis	ec50	0.0001	uM
tert-butyl 2-[(9S)-7-[4-[4-[[4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl]methylcarbamoyl]phenyl]phenyl]-4,5,13-trimethyl-3-thia-1,8,11,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl]acetate	2015586: PROTAC activity at VHL/BRD4 in human LNCaP cells assessed as reduction in protein degradation measured after 6 hrs by Western blot analysis	ec50	0.0001	uM
N-(2-chloro-6-methylphenyl)-2-[[6-[4-[6-[2-[2-[[(2S)-1-[(2S,4R)-4-hydroxy-2-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methylcarbamoyl]pyrrolidin-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]amino]-2-oxoethoxy]ethoxy]hexyl]piperazin-1-yl]-2-methylpyrimidin-4-yl]amino]-1,3-thiazole-5-carboxamide	1678553: Protac binding affinity at VHL/BCR-ABL (unknown origin) assessed as binding to phosphorylated c-ABL kinase domain by Kinomescan assay	kd	0.0002	uM
N-[3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]-4-[4-[[1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]azetidin-3-yl]methyl]piperazin-1-yl]benzamide	1784623: Protac activity at VHL/AR in human VCaP cells assessed as induction of AR degradation measured after 24 hrs by western blot analysis	ec50	0.0002	uM
(2S,4R)-1-[(2S)-2-[[2-[2-[2-[2-[2-[2-[6-[4-[3-[3-cyano-4-(2,4-dichloro-5-methoxyanilino)-6-methoxyquinolin-7-yl]oxypropyl]piperazin-1-yl]hexoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]acetyl]amino]-3,3-dimethylbutanoyl]-4-hydroxy-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide	1678553: Protac binding affinity at VHL/BCR-ABL (unknown origin) assessed as binding to phosphorylated c-ABL kinase domain by Kinomescan assay	kd	0.0003	uM
(2S,4R)-1-[(2S)-2-[[2-[2-[2-[2-[3,5-difluoro-4-[(1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-1,3,4,9-tetrahydropyrido[3,4-b]indol-1-yl]phenoxy]ethoxy]ethoxy]ethoxy]acetyl]amino]-3,3-dimethylbutanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide	1512335: Induction of VHL E3 ligase mediated ERalpha degradation in human MCF7 cells assessed as downregulation of ERalpha expression by cell-based immunofluorescence assay	ic50	0.0003	uM
(2S,4R)-1-[(2S)-2-[[2-[3-[3-[3,5-difluoro-4-[(1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-1,3,4,9-tetrahydropyrido[3,4-b]indol-1-yl]phenoxy]propoxy]propoxy]acetyl]amino]-3,3-dimethylbutanoyl]-4-hydroxy-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide	1512335: Induction of VHL E3 ligase mediated ERalpha degradation in human MCF7 cells assessed as downregulation of ERalpha expression by cell-based immunofluorescence assay	ic50	0.0003	uM
N-[3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]-4-[4-[[1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]piperidin-4-yl]methyl]piperazin-1-yl]benzamide	1784623: Protac activity at VHL/AR in human VCaP cells assessed as induction of AR degradation measured after 24 hrs by western blot analysis	ec50	0.0003	uM
N-[3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]-4-[4-[[4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]piperazin-1-yl]methyl]piperidin-1-yl]benzamide	1784623: Protac activity at VHL/AR in human VCaP cells assessed as induction of AR degradation measured after 24 hrs by western blot analysis	ec50	0.0004	uM
(2S,4R)-1-[(2S)-2-[[2-[3-[2-[3,5-difluoro-4-[(1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-1,3,4,9-tetrahydropyrido[3,4-b]indol-1-yl]phenoxy]ethoxy]propoxy]acetyl]amino]-3,3-dimethylbutanoyl]-4-hydroxy-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide	1512335: Induction of VHL E3 ligase mediated ERalpha degradation in human MCF7 cells assessed as downregulation of ERalpha expression by cell-based immunofluorescence assay	ic50	0.0004	uM
N-(2-chloro-6-methylphenyl)-2-[[6-[4-[6-[2-[2-[6-[[(2S)-1-[(2S,4R)-4-hydroxy-2-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methylcarbamoyl]pyrrolidin-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]amino]-6-oxohexoxy]ethoxy]ethoxy]hexyl]piperazin-1-yl]-2-methylpyrimidin-4-yl]amino]-1,3-thiazole-5-carboxamide	1678553: Protac binding affinity at VHL/BCR-ABL (unknown origin) assessed as binding to phosphorylated c-ABL kinase domain by Kinomescan assay	kd	0.0005	uM
(2S,4R)-1-[(2S)-2-(4-cyclopropyltriazol-1-yl)-3,3-dimethylbutanoyl]-4-hydroxy-N-[(5S)-2-(4-methyl-1,3-thiazol-5-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl]pyrrolidine-2-carboxamide	2072803: Binding affinity to Navi-tagged VHL (unknown origin) assessed as dissociation constant by SPR assay	kd	0.0005	uM
(2S,4R)-1-[(2S)-2-[[2-[2-[5-[3,5-difluoro-4-[(1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-1,3,4,9-tetrahydropyrido[3,4-b]indol-1-yl]phenoxy]pentoxy]ethoxy]acetyl]amino]-3,3-dimethylbutanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide	1512335: Induction of VHL E3 ligase mediated ERalpha degradation in human MCF7 cells assessed as downregulation of ERalpha expression by cell-based immunofluorescence assay	ic50	0.0006	uM
(2S,4R)-1-[(2S)-3,3-dimethyl-2-[[2-[2-[2-[2-[2-[[4-[[4-[4-(pyridin-3-ylmethylcarbamothioylamino)phenyl]sulfonylpiperazin-1-yl]methyl]benzoyl]amino]ethoxy]ethoxy]ethoxy]ethoxy]acetyl]amino]butanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide	2012074: PROTAC activity at VHL/NAMPT in human A2780 cells assessed as protein degradation	ec50	0.0006	uM
(2S,4R)-1-[(2S)-2-[[2-[2-[6-[4-[3-[3-cyano-4-(2,4-dichloro-5-methoxyanilino)-6-methoxyquinolin-7-yl]oxypropyl]piperazin-1-yl]hexoxy]ethoxy]acetyl]amino]-3,3-dimethylbutanoyl]-4-hydroxy-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide	1678553: Protac binding affinity at VHL/BCR-ABL (unknown origin) assessed as binding to phosphorylated c-ABL kinase domain by Kinomescan assay	kd	0.0007	uM
(2R,4S)-1-[(2R)-2-[[2-[3-[2-[2-[2-[[2-[(9R)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl]acetyl]amino]ethoxy]ethoxy]ethoxy]-2-[2-[2-[2-[[2-[(9R)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl]acetyl]amino]ethoxy]ethoxy]ethoxymethyl]-2-methylpropoxy]acetyl]amino]-3,3-dimethylbutanoyl]-4-hydroxy-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide	1946241: Protac activity at VHL/BRD4 in HEK293 cells assessed as degradation of BRD4 incubated for 4 hrs by Western blot analysis	ec50	0.0007	uM
(2S,4R)-N-[(1S)-3-[4-[4-[2-[4-[[3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]carbamoyl]phenyl]ethynyl]piperidin-1-yl]piperidin-1-yl]-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]-3-oxopropyl]-1-[(2S)-2-[(1-fluorocyclopropanecarbonyl)amino]-3,3-dimethylbutanoyl]-4-hydroxypyrrolidine-2-carboxamide	1960582: Protac activity at VHL/AR in human VCaP cells assessed as induction of protein degradation measured after 24 hrs by Western blot analysis	ec50	0.0008	uM
(2S,4R)-1-[(2S)-2-[[2-[2-[5-[3,5-difluoro-4-[(1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-1,3,4,9-tetrahydropyrido[3,4-b]indol-1-yl]phenoxy]-3,3-difluoropentoxy]ethoxy]acetyl]amino]-3,3-dimethylbutanoyl]-4-hydroxy-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide	1512335: Induction of VHL E3 ligase mediated ERalpha degradation in human MCF7 cells assessed as downregulation of ERalpha expression by cell-based immunofluorescence assay	ic50	0.0008	uM
N-[3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]-4-[4-[1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]piperidin-4-yl]piperazin-1-yl]benzamide	1784623: Protac activity at VHL/AR in human VCaP cells assessed as induction of AR degradation measured after 24 hrs by western blot analysis	ec50	0.0008	uM
(2S,4R)-1-[(2S)-2-[[2-[3-[2-[[2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl]acetyl]amino]ethoxy]propoxy]acetyl]amino]-3,3-dimethylbutanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide	1939893: Protac activity at BRD2/VHL-bound E3 ligase in human 22Rv1 cells assessed as reduction c-Myc level incubated for 24 hrs by Western blot analysis	ic50	0.0010	uM
6-[3-(1,3-benzothiazol-2-ylamino)-4-methyl-6,7-dihydro-5H-pyrido[2,3-c]pyridazin-8-yl]-3-[1-[[(5S,7R)-3-[2-[[16-[[(2S)-1-[(2S,4R)-4-hydroxy-2-[[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]carbamoyl]pyrrolidin-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]amino]-16-oxohexadecyl]-methylamino]ethoxy]-5,7-dimethyl-1-adamantyl]methyl]-5-methylpyrazol-4-yl]pyridine-2-carboxylic acid	1968806: Protac activity at VHL/BCL-xl in human NCI-H1650 cells assessed as induction of BCL-xl degradation by Nano-Glo HiBiT assay	ec50	0.0010	uM
6-[3-(1,3-benzothiazol-2-ylamino)-4-methyl-6,7-dihydro-5H-pyrido[2,3-c]pyridazin-8-yl]-3-[1-[[(5S,7R)-3-[2-[[12-[[(2S)-1-[(2S,4R)-4-hydroxy-2-[[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]carbamoyl]pyrrolidin-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]amino]-12-oxododecyl]-methylamino]ethoxy]-5,7-dimethyl-1-adamantyl]methyl]-5-methylpyrazol-4-yl]pyridine-2-carboxylic acid	1968806: Protac activity at VHL/BCL-xl in human NCI-H1650 cells assessed as induction of BCL-xl degradation by Nano-Glo HiBiT assay	ec50	0.0010	uM
6-[3-(1,3-benzothiazol-2-ylamino)-4-methyl-6,7-dihydro-5H-pyrido[2,3-c]pyridazin-8-yl]-3-[1-[[(5S,7R)-3-[2-[[15-[[(2S)-1-[(2S,4R)-4-hydroxy-2-[[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]carbamoyl]pyrrolidin-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]amino]-15-oxopentadecyl]-methylamino]ethoxy]-5,7-dimethyl-1-adamantyl]methyl]-5-methylpyrazol-4-yl]pyridine-2-carboxylic acid	1968806: Protac activity at VHL/BCL-xl in human NCI-H1650 cells assessed as induction of BCL-xl degradation by Nano-Glo HiBiT assay	ec50	0.0010	uM
(2R,4S)-4-hydroxy-1-[(2R)-2-[5-[4-[2-[[4-[6-hydroxy-2-(4-hydroxyphenyl)-1-benzothiophene-3-carbonyl]benzoyl]amino]ethyl]phenoxy]pentanoylamino]-3,3-dimethylbutanoyl]-N-[(1R)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide	1946250: Protac activity at VHL/ER alpha in human MCF7 cells assessed as degradation of ER alpha incubated for 6 hrs by Western blot analysis	ec50	0.0011	uM
(2S,4R)-1-[(2S)-3,3-dimethyl-2-[[2-[2-[2-[2-[2-[4-[propyl-[(2R)-2-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]benzoyl]amino]propyl]amino]butoxy]ethoxy]ethoxy]ethoxy]ethoxy]acetyl]amino]butanoyl]-4-hydroxy-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide	1875228: Protac activity at VHL/HDAC4 in human Jurkat E6.1 cells assessed as induction of HDAC4 degradation preincubated with elacridar for 1 hr followed by compound addition and measured after 24 hrs by Western blot analysis	ec50	0.0016	uM
(2S,4R)-N-[[2-[5-[4-[[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl]piperazin-1-yl]pentoxy]-4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]-1-[(2S)-2-[(1-fluorocyclopropanecarbonyl)amino]-3,3-dimethylbutanoyl]-4-hydroxypyrrolidine-2-carboxamide	1960449: PROTAC activity at VHL/BRD9 in human Ri-1 cells assessed as degradation of BRD9 protein incubated for 8 hrs by Western blot analysis	ec50	0.0018	uM
6-[3-(1,3-benzothiazol-2-ylamino)-4-methyl-6,7-dihydro-5H-pyrido[2,3-c]pyridazin-8-yl]-3-[1-[[(5S,7R)-3-[2-[[9-[[(2S)-1-[(2S,4R)-4-hydroxy-2-[[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]carbamoyl]pyrrolidin-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]amino]-9-oxononyl]-methylamino]ethoxy]-5,7-dimethyl-1-adamantyl]methyl]-5-methylpyrazol-4-yl]pyridine-2-carboxylic acid	1968806: Protac activity at VHL/BCL-xl in human NCI-H1650 cells assessed as induction of BCL-xl degradation by Nano-Glo HiBiT assay	ec50	0.0020	uM
(4S)-1-[(2S)-2-[[2-[2-[2-[2-[2-[4-(1,3-benzothiazol-5-ylamino)-6-tert-butylsulfonylquinolin-7-yl]oxyethoxy]ethoxy]ethoxy]ethoxy]acetyl]amino]-3,3-dimethylbutanoyl]-4-hydroxy-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide	2137475: Protac activity at VHL/RIPK2 in human THP-1 cells assessed as RIPK2 degradation measured after 16 hrs by Western blot analysis	ic50	0.0020	uM
(2S,4R)-1-[(2S)-2-(1-adamantyl)-2-(4-cyclopropyltriazol-1-yl)acetyl]-4-hydroxy-N-[(2S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]propan-2-yl]pyrrolidine-2-carboxamide	2072801: Binding affinity to VHL (unknown origin)-NanoLuc fusion protein expressed in HEK293 cells assessed as apparent dissociation constant incubated for 2 hrs by NanoBRET assay	kd	0.0025	uM
(2S,4R)-1-[(2S)-2-[[2-[3-[2-[[2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl]acetyl]amino]ethoxy]propoxy]acetyl]amino]-3,3-dimethylbutanoyl]-4-hydroxy-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide	1813763: Binding affinity to N-terminal His6-tagged VHL (54 to 213 residues)/BRD4 BD2 (333 to 460 residues) (unknown origin) expressed in Escherichia coli assessed as displacement of HIF-1alpha preincubated with Brd4 BD2 by ternary binding competitive fluorescence polarization assay	kd	0.0030	uM
(2S,4R)-1-[(2S)-3,3-dimethyl-2-[3-[2-[4-[[4-[[3-[methyl(methylsulfonyl)amino]phenyl]methylamino]-5-(trifluoromethyl)pyrimidin-2-yl]amino]phenoxy]ethoxy]propanoylamino]butanoyl]-4-hydroxy-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide	1849960: PROTAC activity at VHL/FAK in human PC-3 cells assessed as induction of FAK degradation incubated for 24 hrs by immunoblot analysis	ec50	0.0030	uM
(2S,4R)-1-[(2S)-3,3-dimethyl-2-[[2-[2-[2-[4-[propyl-[(2R)-2-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]benzoyl]amino]propyl]amino]butoxy]ethoxy]ethoxy]acetyl]amino]butanoyl]-4-hydroxy-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide	1875210: Protac activity at VHL/HDAC4 in human Jurkat E6.1 cells assessed as induction of HDAC4 degradation incubated for 24 hrs by ELISA-based MSD electrochemiluminescence assay	ec50	0.0030	uM
6-[3-(1,3-benzothiazol-2-ylamino)-4-methyl-6,7-dihydro-5H-pyrido[2,3-c]pyridazin-8-yl]-3-[1-[[(5S,7R)-3-[2-[[8-[[(2S)-1-[(2S,4R)-4-hydroxy-2-[[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]carbamoyl]pyrrolidin-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]amino]-8-oxooctyl]-methylamino]ethoxy]-5,7-dimethyl-1-adamantyl]methyl]-5-methylpyrazol-4-yl]pyridine-2-carboxylic acid	1968806: Protac activity at VHL/BCL-xl in human NCI-H1650 cells assessed as induction of BCL-xl degradation by Nano-Glo HiBiT assay	ec50	0.0030	uM
6-[3-(1,3-benzothiazol-2-ylamino)-4-methyl-6,7-dihydro-5H-pyrido[2,3-c]pyridazin-8-yl]-3-[1-[[(5S,7R)-3-[2-[[7-[[(2S)-1-[(2S,4R)-4-hydroxy-2-[[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]carbamoyl]pyrrolidin-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]amino]-7-oxoheptyl]-methylamino]ethoxy]-5,7-dimethyl-1-adamantyl]methyl]-5-methylpyrazol-4-yl]pyridine-2-carboxylic acid	1968806: Protac activity at VHL/BCL-xl in human NCI-H1650 cells assessed as induction of BCL-xl degradation by Nano-Glo HiBiT assay	ec50	0.0030	uM
(2S,4R)-1-[(2S)-2-(4-cyclopropyltriazol-1-yl)-3,3-dimethylbutanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide	2072801: Binding affinity to VHL (unknown origin)-NanoLuc fusion protein expressed in HEK293 cells assessed as apparent dissociation constant incubated for 2 hrs by NanoBRET assay	kd	0.0033	uM
(2R,4S)-N-[[2-[2-[4-[[4-[3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl]piperazin-1-yl]methyl]phenoxy]ethoxy]-4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]-1-[(2R)-2-[(1-fluorocyclopropanecarbonyl)amino]-3,3-dimethylbutanoyl]-4-hydroxypyrrolidine-2-carboxamide	1928111: PROTAC activity at SMARCA2/VHL in human NCI-H1568 cells assessed as degradation protein measured after 18 hrs	ec50	0.0033	uM
(2S,4R)-1-[(2R)-2-[3-[2-[4-[3-[[4-[3-[3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-pyridinyl]oxy]cyclobutyl]oxypiperidin-1-yl]ethoxy]-1,2-oxazol-5-yl]-3-methylbutanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide	2098176: Binding affinity to VHL (unknown origin) assessed as dissociation constant	kd	0.0034	uM
(2S,4R)-1-[(2S)-2-[11-[4-[[4-(3-chloro-4-fluoroanilino)-6-[[(E)-4-piperidin-1-ylbut-2-enoyl]amino]quinazolin-7-yl]oxymethyl]triazol-1-yl]undecanoylamino]-3,3-dimethylbutyl]-4-hydroxy-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide	1967999: Protac activity at VHL/EGFR deletion19 mutant in human HCC827 cells assessed as induction of protein degradation	ec50	0.0036	uM
(2S,4R)-1-[(2S)-2-[[2-[5-[2-[[2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl]acetyl]amino]ethoxy]pentoxy]acetyl]amino]-3,3-dimethylbutanoyl]-4-hydroxy-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide	1813763: Binding affinity to N-terminal His6-tagged VHL (54 to 213 residues)/BRD4 BD2 (333 to 460 residues) (unknown origin) expressed in Escherichia coli assessed as displacement of HIF-1alpha preincubated with Brd4 BD2 by ternary binding competitive fluorescence polarization assay	kd	0.0037	uM
(2S,4R)-1-[(2S)-3,3-dimethyl-2-[[2-[2-[2-[2-[4-[propyl-[(2R)-2-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]benzoyl]amino]propyl]amino]butoxy]ethoxy]ethoxy]ethoxy]acetyl]amino]butanoyl]-4-hydroxy-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide	1875210: Protac activity at VHL/HDAC4 in human Jurkat E6.1 cells assessed as induction of HDAC4 degradation incubated for 24 hrs by ELISA-based MSD electrochemiluminescence assay	ec50	0.0040	uM
(2S,4R)-1-[(2S)-2-[[2-[2-[2-[2-[[2-[7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl]acetyl]amino]ethoxy]ethoxy]ethoxy]acetyl]amino]-3,3-dimethylbutanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide	2020703: PROTAC activity at BRD4/VHL E3 ligase in human MDA-MB-231 cells assessed as decrease in BRD4 expression incubated for 48 hrs by Western blot analysis	ec50	0.0040	uM
(2S,4R)-4-hydroxy-1-[(2S)-2-[4-[4-[3-[2-[4-[(Z)-1-(4-hydroxyphenyl)-2-phenylbut-1-enyl]phenoxy]ethyl-methylamino]-3-oxopropyl]triazol-1-yl]butanoylamino]-3,3-dimethylbutanoyl]-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide	1991577: PROTAC activity at VHL E3 ligase/ERalpha in human MCF7 cells assessed as reduction in ERalpha protein level incubated for 24 hrs by Western blot analysis	ec50	0.0045	uM
2-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydro-1H-isoquinolin-2-yl]-5-[3-[4-[3-[2-[2-[2-[2-[2-[3-[[(2S)-1-[(2S,4R)-4-hydroxy-2-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methylcarbamoyl]pyrrolidin-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]amino]-3-oxopropoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]prop-1-ynyl]phenoxy]propyl]-1,3-thiazole-4-carboxylic acid	1853853: PROTAC activity at VHL/Bcl-xL in human THP-1 cells assessed as induction of Bcl-xL degradation incubated for 24 hrs by Western blot assay	ec50	0.0048	uM
(2S,4R)-1-[(2S)-2-[3-[2-[2-[2-[4-[(5-tert-butyl-1,2-oxazol-3-yl)carbamoylamino]phenyl]imidazo[2,1-b][1,3]benzothiazol-6-yl]oxyethoxy]ethoxy]propanoylamino]-3,3-dimethylbutanoyl]-4-hydroxy-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide	2031638: PROTAC activity at VHL/FLT3 in human MV4-11 cells assessed as induction of FLT3 degradation by Western blot analysis	ec50	0.0050	uM
(2S,4R)-N-[[2-[2-[2-[2-[4-[6-[(6-acetyl-8-cyclopentyl-5-methyl-7-oxopyrido[2,3-d]pyrimidin-2-yl)amino]-3-pyridinyl]piperazin-1-yl]ethoxy]ethoxy]ethoxy]-4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]-1-[(2S)-2-[(1-fluorocyclopropanecarbonyl)amino]-3,3-dimethylbutanoyl]-4-hydroxypyrrolidine-2-carboxamide	2031640: PROTAC activity at VHL/CDK6 in human MV4-11 cells assessed as induction of CDK6 degradation by Western blot analysis	ec50	0.0051	uM
(2R,4S)-N-[[2-[2-[2-[2-[4-[6-[(6-acetyl-8-cyclopentyl-5-methyl-7-oxopyrido[2,3-d]pyrimidin-2-yl)amino]-3-pyridinyl]piperazin-1-yl]ethoxy]ethoxy]ethoxy]-4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]-1-[(2S)-2-[(1-fluorocyclopropanecarbonyl)amino]-3,3-dimethylbutanoyl]-4-hydroxypyrrolidine-2-carboxamide	1849954: PROTAC activity at VHL/CDK6 in human MM1.S cells assessed as induction of CDK6 degradation incubated for 16 hrs by Western blot analysis	ec50	0.0051	uM
(2S,4R)-N-[[2-[2-[2-[2-[4-[6-[[(6E)-8-cyclopentyl-6-(1-hydroxyethylidene)-5-methyl-7-oxo-5H-pyrido[2,3-d]pyrimidin-2-yl]amino]-3-pyridinyl]piperazin-1-yl]ethoxy]ethoxy]ethoxy]-4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]-1-[2-[(1-fluorocyclopropanecarbonyl)amino]-3,3-dimethylbutanoyl]-4-hydroxypyrrolidine-2-carboxamide	1946251: Protac activity at VHL/CDK6 in human MM1.S cells assessed as degradation of CDK6 incubated for 16 hrs by immunoblot assay	ec50	0.0051	uM
(2S,4R)-4-hydroxy-1-[(2S)-2-[6-[4-[3-[2-[4-[(Z)-1-(4-hydroxyphenyl)-2-phenylbut-1-enyl]phenoxy]ethyl-methylamino]-3-oxopropyl]triazol-1-yl]hexanoylamino]-3,3-dimethylbutanoyl]-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide	1991577: PROTAC activity at VHL E3 ligase/ERalpha in human MCF7 cells assessed as reduction in ERalpha protein level incubated for 24 hrs by Western blot analysis	ec50	0.0053	uM
(2S,4R)-1-[(2S)-2-(4-cyclopropyltriazol-1-yl)-3,3-dimethylbutanoyl]-4-hydroxy-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide	2072801: Binding affinity to VHL (unknown origin)-NanoLuc fusion protein expressed in HEK293 cells assessed as apparent dissociation constant incubated for 2 hrs by NanoBRET assay	kd	0.0063	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases reaction, increases hydroxylation, increases reaction, decreases degradation, increases expression (+2 more)	4
Oxygen	affects binding, affects cotreatment, decreases reaction, increases expression, increases reaction (+4 more)	4
Cadmium	affects binding, decreases reaction, increases abundance, increases expression, decreases expression	3
Cadmium Chloride	increases expression, decreases expression, affects binding, decreases reaction, increases abundance	3
nickel chloride	affects cotreatment, increases expression, affects binding, decreases reaction	2
benzyloxycarbonylleucyl-leucyl-leucine aldehyde	affects binding, affects cotreatment, increases reaction, decreases reaction	2
Decitabine	increases expression, increases reaction, affects expression, decreases expression, decreases reaction (+1 more)	2
Hydrogen Peroxide	affects expression, affects reaction, decreases response to substance, affects response to substance	2
Quercetin	affects binding, decreases reaction, increases reaction, increases expression	2
Smoke	decreases expression, increases abundance	2
Trichloroethylene	increases mutagenesis	2
1-cyclopropyl-4-(4-((5-methyl-3-(3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5-yl)-1H-pyrazol-1-yl)methyl)pyridin-2-yl)piperazine	increases response to substance	1
beta-lapachone	decreases expression	1
11-nor-delta(9)-tetrahydrocannabinol-9-carboxylic acid	affects methylation, increases abundance	1
manganese chloride	affects cotreatment, decreases reaction, increases reaction, affects reaction, increases expression (+1 more)	1
ferrous chloride	increases reaction, decreases reaction, affects binding, affects cotreatment	1
beta-methylcholine	affects expression	1
arsenic disulfide	increases methylation	1
di-n-butylphosphoric acid	affects expression	1
motexafin gadolinium	increases expression, decreases reaction	1
ICG 001	increases expression	1
3,5-bis(2-fluorobenzylidene)piperidin-4-one	increases reaction, decreases expression	1
4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acid	increases expression	1
Resveratrol	affects cotreatment, increases expression	1
Air Pollutants	decreases expression, increases abundance	1
Arsenic	affects methylation	1
Ascorbic Acid	affects cotreatment, increases reaction, decreases reaction, affects binding	1
Atrazine	decreases expression	1
Benzo(a)pyrene	affects methylation, increases methylation	1
Cannabinoids	affects methylation, increases abundance	1

ChEMBL screening assays

3575 unique, capped per target: 3482 binding, 54 functional, 39 admet

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3110591	Binding	Displacement of 19-mer HIF-1alpha peptide from VHL (unknown origin) by isothermal titration calorimetry analysis	Is NMR Fragment Screening Fine-Tuned to Assess Druggability of Protein-Protein Interactions? — ACS Med Chem Lett
CHEMBL5374656	Functional	In vivo PROTAC activity at BRD4/VHL E3 ligase in BALB/c nude mouse xenografted with human MCF7 cells assessed as reduction in BRD4 protein level in tumor 20 mg/kg measured after 48 hrs by Western blot analysis	Rational Design of Bioorthogonally Activatable PROTAC for Tumor-Targeted Protein Degradation. — J Med Chem
CHEMBL5328366	ADMET	In vivo PROTAC activity at VHL/SMARCA4 in SCID mouse xenografted with human MV4-11 cells assessed as reduction of SMARCA4 level in tumor at 50 mg/kg, iv administered as single dose measured after 2 hrs by Western blotting analysis	Discovery of SMD-3040 as a Potent and Selective SMARCA2 PROTAC Degrader with Strong in vivo Antitumor Activity. — J Med Chem

Cellosaurus cell lines

120 cell lines: 110 cancer cell line, 5 induced pluripotent stem cell, 3 embryonic stem cell, 2 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_0498	RCC4	Cancer cell line	Sex unspecified
CVCL_1051	786-O	Cancer cell line	Male
CVCL_1056	A-498	Cancer cell line	Male
CVCL_1486	NCI-H1672	Cancer cell line	Male
CVCL_1555	NCI-H28	Cancer cell line	Male
CVCL_1791	VMRC-RCZ	Cancer cell line	Sex unspecified
CVCL_2706	RCC4/VHL	Cancer cell line	Sex unspecified
CVCL_2739	UM-RC-2	Cancer cell line	Sex unspecified
CVCL_2740	UM-RC-3	Cancer cell line	Sex unspecified
CVCL_2741	UM-RC-6	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00414765	PHASE4	COMPLETED	Aldesleukin in Participants With Metastatic Renal Cell Carcinoma or Metastatic Melanoma
NCT00777504	PHASE4	UNKNOWN	Study to the Optimal Duration of Therapy With Oral Angiogenesis Inhibitors
NCT00930345	PHASE4	TERMINATED	Biological, Pathological and Imagery Markers in the First-line Treatment of Metastatic Clear-cell Renal Cell Carcinoma
NCT01206764	PHASE4	COMPLETED	A Trial of Everolimis in Patients With Advanced Renal Cell Carcinoma.
NCT01266837	PHASE4	COMPLETED	Open Label, Single Arm Trial to Characterize Patients With Metastatic RCC Treated With Everolimus After Failure of the First VEGF-targeted Therapy (MARC-2)
NCT02056587	PHASE4	COMPLETED	Everolimus in Patients With Metastatic Renal Cell Carcinoma Following Progression on Prior Bevacizumab Treatment
NCT02338570	PHASE4	TERMINATED	Outcome-related Factors in Patients With Metastatic Renal Cell Carcinoma Treated With Everolimus (ORCHIDEE)
NCT02596035	PHASE4	COMPLETED	An Investigational Immuno-therapy Safety Trial of Nivolumab in Patients With Advanced or Metastatic Renal Cell Carcinoma
NCT02982954	PHASE4	COMPLETED	A Study to Evaluate the Safety of Nivolumab and Ipilimumab in Subjects With Previously Untreated Advanced or Metastatic Renal Cell Cancer
NCT05949424	PHASE4	UNKNOWN	OPTI - DOSE: Optimal Dosing of Oral Anticancer Drugs in Older Adults
NCT07028125	PHASE4	RECRUITING	Digital Monitoring of Self-reported Symptoms by Patients Treated With Cabozantinib Plus Nivolumab for Advanced Clear-cell Renal Carcinoma
NCT07405086	PHASE4	RECRUITING	Morning Versus Afternoon Administration of Immunotherapy for the Treatment of Advanced or Metastatic Solid Tumors, The Knight SHIFT Study
NCT07405164	PHASE3	RECRUITING	Extension Study for Participants in Studies That Include Belzutifan (MK-6482-043/LITESPARK-043)
NCT00033904	PHASE3	COMPLETED	Survival Study Of Oncophage® vs. Observation In Patients With Kidney Cancer
NCT00126178	PHASE3	TERMINATED	Clinical Trial Studying a Personalized Cancer Vaccine in Patients With Non-metastatic Kidney Cancer
NCT00291369	PHASE3	COMPLETED	Cytokines in Patients With Metastatic Renal Cell Carcinoma of Intermediate Prognosis
NCT00410124	PHASE3	COMPLETED	RAD001 Plus Best Supportive Care (BSC) Versus BSC Plus Placebo in Patients With Metastatic Carcinoma of the Kidney Which Has Progressed After Treatment With Sorafenib and/or Sunitinib
NCT00474786	PHASE3	COMPLETED	Temsirolimus Versus Sorafenib As Second-Line Therapy In Patients With Advanced RCC Who Have Failed First-Line Sunitinib
NCT00478114	PHASE3	COMPLETED	Efficacy and Safety of Sorafenib in Advanced Renal Cell Carcinoma (RCC)
NCT00606632	PHASE3	COMPLETED	Pre-surgical Detection of Clear Cell Renal Cell Carcinoma (ccRCC) Using Radiolabeled G250-Antibody
NCT00606866	PHASE3	COMPLETED	MRI Study of BAY 43-9006 in Metastatic Renal Cell Carcinoma
NCT00631371	PHASE3	COMPLETED	Study Comparing Bevacizumab + Temsirolimus vs. Bevacizumab + Interferon-Alfa In Advanced Renal Cell Carcinoma Subjects
NCT00732914	PHASE3	COMPLETED	Sequential Study to Treat Renal Cell Carcinoma
NCT00869011	PHASE3	UNKNOWN	Exercise for Patients With Renal Cell Cancer Receiving Sunitinib
NCT00930033	PHASE3	COMPLETED	Clinical Trial to Assess the Importance of Nephrectomy
NCT01030783	PHASE3	COMPLETED	A Study to Compare Tivozanib (AV-951) to Sorafenib in Subjects With Advanced Renal Cell Carcinoma
NCT01076010	PHASE3	COMPLETED	An Extension Treatment Protocol for Subjects Who Have Participated in a Study of Tivozanib Versus Sorafenib in Kidney Carcinoma (Protocol AV-951-09-301).
NCT01198158	PHASE3	TERMINATED	Everolimus With or Without Bevacizumab in Treating Patients With Advanced Kidney Cancer That Progressed After First-Line Therapy
NCT01223027	PHASE3	COMPLETED	Study of Dovitinib Versus Sorafenib in Patients With Metastatic Renal Cell Carcinoma
NCT01224288	PHASE3	ACTIVE_NOT_RECRUITING	Dynamic Contrast Enhancement Computed Tomography for Evaluating Tumor Perfusion in Patients With Metastatic Renal Cell Carcinoma Receiving Targeted Therapies: Renal Cell Carcinoma (RCC) Scramble
NCT01235962	PHASE3	COMPLETED	A Study to Evaluate Pazopanib as an Adjuvant Treatment for Localized Renal Cell Carcinoma (RCC)
NCT01265810	PHASE3	COMPLETED	Caphosol in Oral Mucositis Due to Targeted Therapy
NCT01265901	PHASE3	COMPLETED	IMA901 in Patients Receiving Sunitinib for Advanced/Metastatic Renal Cell Carcinoma
NCT01481870	PHASE3	UNKNOWN	Comparison of Sequential Therapies With Sunitinib and Sorafenib in Advanced Renal Cell Carcinoma
NCT01582672	PHASE3	TERMINATED	Phase 3 Trial of Autologous Dendritic Cell Immunotherapy Plus Standard Treatment of Advanced Renal Cell Carcinoma
NCT01613846	PHASE3	COMPLETED	Phase III Sequential Open-label Study to Evaluate the Efficacy and Safety of Sorafenib Followed by Pazopanib Versus Pazopanib Followed by Sorafenib in the Treatment of Advanced / Metastatic Renal Cell Carcinoma (SWITCH-II)
NCT01762592	PHASE3	WITHDRAWN	REDECT 2: REnal Masses: Pivotal Trial to DEteCT Clear Cell Renal Cell Carcinoma With PET/CT
NCT01865747	PHASE3	COMPLETED	A Study of Cabozantinib (XL184) vs Everolimus in Subjects With Metastatic Renal Cell Carcinoma
NCT02231749	PHASE3	COMPLETED	Nivolumab Combined With Ipilimumab Versus Sunitinib in Previously Untreated Advanced or Metastatic Renal Cell Carcinoma (CheckMate 214)
NCT02420821	PHASE3	COMPLETED	A Study of Atezolizumab in Combination With Bevacizumab Versus Sunitinib in Participants With Untreated Advanced Renal Cell Carcinoma (RCC)