RET

Summary

RET (ret proto-oncogene, HGNC:9967) is a protein-coding gene on chromosome 10q11.21, encoding Proto-oncogene tyrosine-protein kinase receptor Ret (P07949). Receptor tyrosine-protein kinase involved in numerous cellular mechanisms including cell proliferation, neuronal navigation, cell migration, and cell differentiation in response to glia cell line-derived growth family factors (GDNF, NRTN, ARTN, PSPN and GDF15). In precision oncology, RET Mutation confers sensitivity to Selpercatinib in Medullary Thyroid Carcinoma (CIViC Level A); 28 further curated variant–drug associations are listed below. It is haploinsufficient (ClinGen: sufficient evidence).

This gene encodes a transmembrane receptor and member of the tyrosine protein kinase family of proteins. Binding of ligands such as GDNF (glial cell-line derived neurotrophic factor) and other related proteins to the encoded receptor stimulates receptor dimerization and activation of downstream signaling pathways that play a role in cell differentiation, growth, migration and survival. The encoded receptor is important in development of the nervous system, and the development of organs and tissues derived from the neural crest. This proto-oncogene can undergo oncogenic activation through both cytogenetic rearrangement and activating point mutations. Mutations in this gene are associated with Hirschsprung disease and central hypoventilation syndrome and have been identified in patients with renal agenesis.

Source: NCBI Gene 5979 — RefSeq curated summary.

At a glance

• Gene–disease (curated): multiple endocrine neoplasia type 2B (Definitive, ClinGen) — +9 more curated relationships
• GWAS associations: 14
• Clinical variants (ClinVar): 4,311 total — 103 pathogenic, 46 likely-pathogenic
• Phenotypes (HPO): 136
• Druggable target: yes — 135 molecules with ChEMBL bioactivity
• Precision-oncology evidence (CIViC): 29 curated variant–drug associations
• Cancer driver (intOGen): activating (oncogene-like) across 6 cancer types
• Dosage sensitivity (ClinGen): haploinsufficiency sufficient evidence, triplosensitivity no evidence
• MANE Select transcript: NM_020975

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9967
Approved symbol	RET
Name	ret proto-oncogene
Location	10q11.21
Locus type	gene with protein product
Status	Approved
Aliases	PTC, CDHF12, RET51, CDHR16
Ensembl gene	ENSG00000165731
Ensembl biotype	protein_coding
OMIM	164761
Entrez	5979

Gene structure

Transcript identifiers

Ensembl transcripts: 17 — 13 protein_coding, 2 nonsense_mediated_decay, 2 retained_intron

ENST00000340058, ENST00000355710, ENST00000498820, ENST00000615310, ENST00000638465, ENST00000640619, ENST00000671844, ENST00000672389, ENST00000683007, ENST00000683278, ENST00000683872, ENST00000684216, ENST00000713926, ENST00000935252, ENST00000935253, ENST00000935254, ENST00000935255

RefSeq mRNA: 41 — MANE Select: NM_020975 NM_001355216, NM_001406743, NM_001406744, NM_001406759, NM_001406760, NM_001406761, NM_001406762, NM_001406763, NM_001406764, NM_001406765, NM_001406766, NM_001406767, NM_001406768, NM_001406769, NM_001406770, NM_001406771, NM_001406772, NM_001406773, NM_001406774, NM_001406775, NM_001406776, NM_001406777, NM_001406778, NM_001406779, NM_001406780, NM_001406781, NM_001406782, NM_001406783, NM_001406784, NM_001406785, NM_001406786, NM_001406787, NM_001406788, NM_001406789, NM_001406790, NM_001406791, NM_001406792, NM_001406793, NM_001406794, NM_020630, NM_020975

CCDS: CCDS53525, CCDS7200

Canonical transcript exons

ENST00000355710 — 20 exons

Exon	Start	End
ENSE00001095904	43109031	43109230
ENSE00001095907	43106376	43106571
ENSE00001095923	43102342	43102629
ENSE00001095944	43116584	43116731
ENSE00001095946	43104952	43105193
ENSE00001164770	43118373	43118480
ENSE00001164787	43114480	43114736
ENSE00001164798	43113556	43113675
ENSE00001164807	43112853	43112963
ENSE00001164816	43112099	43112224
ENSE00001312192	43111207	43111465
ENSE00001365997	43100459	43100722
ENSE00001386034	43128112	43130351
ENSE00002442774	43123671	43123808
ENSE00002444663	43124883	43124982
ENSE00002515890	43121946	43122016
ENSE00004021789	43126575	43126722
ENSE00004021792	43119531	43119745
ENSE00004021793	43120081	43120203
ENSE00004021796	43077069	43077331

Expression profiles

Bgee: expression breadth ubiquitous, 193 present calls, max score 91.87.

FANTOM5 (CAGE): breadth broad, TPM avg 3.6163 / max 341.4287, expressed in 481 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
104739	3.6163	481

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
substantia nigra pars reticulata	UBERON:0001966	91.87	gold quality
dorsal root ganglion	UBERON:0000044	91.53	gold quality
substantia nigra pars compacta	UBERON:0001965	90.73	gold quality
trigeminal ganglion	UBERON:0001675	82.58	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	81.60	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	81.03	gold quality
substantia nigra	UBERON:0002038	80.27	gold quality
midbrain	UBERON:0001891	79.30	gold quality
pancreatic ductal cell	CL:0002079	78.66	silver quality
pons	UBERON:0000988	77.27	gold quality
tibialis anterior	UBERON:0001385	76.98	silver quality
endometrium epithelium	UBERON:0004811	76.11	gold quality
lateral nuclear group of thalamus	UBERON:0002736	74.36	gold quality
gingival epithelium	UBERON:0001949	73.98	gold quality
hindlimb stylopod muscle	UBERON:0004252	73.64	gold quality
primary visual cortex	UBERON:0002436	72.97	gold quality
superior vestibular nucleus	UBERON:0007227	72.79	gold quality
parotid gland	UBERON:0001831	72.60	silver quality
cerebellar vermis	UBERON:0004720	72.38	silver quality
superficial temporal artery	UBERON:0001614	72.12	gold quality
prefrontal cortex	UBERON:0000451	71.62	gold quality
ileal mucosa	UBERON:0000331	71.01	silver quality
hypothalamus	UBERON:0001898	70.96	gold quality
right adrenal gland	UBERON:0001233	70.50	gold quality
biceps brachii	UBERON:0001507	69.95	silver quality
stromal cell of endometrium	CL:0002255	69.84	gold quality
adrenal gland	UBERON:0002369	69.72	gold quality
left adrenal gland	UBERON:0001234	69.50	gold quality
right adrenal gland cortex	UBERON:0035827	69.37	gold quality
muscle layer of sigmoid colon	UBERON:0035805	69.25	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-CURD-114	yes	11.52
E-HCAD-25	yes	8.96
E-ANND-3	no	3.80

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AR, ASCL1, CTNNB1, EGR1, EGR2, ESR1, FOXA1, FOXC1, HOXB5, NKX2-1, NR4A2, PAX2, PAX3, PAX8, PHOX2A, PHOX2B, PREB, RARG, RUNX1, SOX10, SP1, SP3, TFAP2A, TFAP2C, TFCP2, TLX2, TTF1

miRNA regulators (miRDB)

105 targeting RET, 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-6867-5P	100.00	82.21	3464
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-196A-5P	100.00	68.16	684
HSA-MIR-196B-5P	100.00	68.16	681
HSA-MIR-4455	100.00	65.48	1587
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-103A-3P	99.98	69.14	1595
HSA-MIR-107	99.98	69.14	1595
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-485-3P	99.98	70.68	1585
HSA-MIR-539-3P	99.98	70.74	1616
HSA-MIR-4715-3P	99.98	66.03	670
HSA-MIR-548AA	99.96	70.64	3753
HSA-MIR-548AP-3P	99.96	70.64	3753
HSA-MIR-548T-3P	99.96	70.64	3753
HSA-MIR-3605-5P	99.96	67.12	932
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-128-3P	99.95	71.17	2484
HSA-MIR-216A-3P	99.95	71.19	2505
HSA-MIR-144-3P	99.94	73.98	2698
HSA-MIR-9983-3P	99.94	71.48	3631
HSA-MIR-218-5P	99.93	72.22	2103
HSA-MIR-497-5P	99.92	71.83	2674
HSA-MIR-15A-5P	99.90	72.80	2787
HSA-MIR-15B-5P	99.90	72.78	2798

Functional genomics

ClinGen dosage: haploinsufficiency 3 (sufficient evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• The presence of coiled-coil domains in the ktn1/ret fusion protein (PTC8) suggests ligand-independent dimerization and thus constitutive activation of the ret tyrosine kinase domain. (PMID:10850414)
• Three new somatic cell missense mutations of the RET proto-oncogene associated with sporadic medullary thyroid carcinoma (MTC). (PMID:11692159)
• A germline RET mutation at codon 603 in exon 10 is associated with both medullary and nonmedullary thyroid cancer in a kindred. (PMID:11746981)
• Differentiation of cardiac ganglionic cells is affected, after RETINOIC ACID treatment, by the down-regulation of c-Ret. (PMID:11803116)
• RET oligonucleotide microarray for the detection of RET mutations in multiple endocrine neoplasia type 2 syndromes (PMID:11839664)
• The finding of a somatic deletion in RET exon 15 clarified the sporadic nature of a medullary thyroid carcinoma suspected to be familial. A 12 bp deletion within the catalytic domain of the protooncogene RET. (PMID:11883863)
• role in regulating rac activity and lamellipodia formation (PMID:11886862)
• early detection of RET proto-oncogene mutation is crucial for prevention of thyroidectomy in multiple endocrine neoplasia type 2 children (PMID:11900218)
• if the association between Hashimoto’s thyroiditis and thyroid cancer exists, its molecular basis is different from RET/PTC rearrangement (PMID:11927965)
• Familial medullary thyroid carcinoma: clinical variability and low aggressiveness associated with RET mutation at codon 804. (PMID:11932300)
• family in which the MEN 2A and the HSCR phenotypes are associated with a single point mutation in exon 10 of the RET proto-oncogene. polymorphic sequence variants of the RET proto-oncogene. (PMID:11935126)
• germline mutation of the RET proto-oncogene in members of Slovak families with multiple endocrine neoplasia 2 (PMID:11949835)
• Segregation at three loci explains familial and population risk in Hirschsprung disease. We show oligogenic inheritance of S-HSCR, the 3p21 and 19q12 loci as RET-dependent modifiers, and a parent-of-origin effect at RET. (PMID:11953745)
• Dissecting Hirschsprung disease. RET is the main gene conferring susceptibility. (PMID:11953748)
• These observations lend support to the idea that both RET alleles have a role in pathogenesis of Hirschsprung’s disease, in a dose-dependent fashion. We also showed that the c135G/A polymorphism modifies the phenotype. (PMID:11955539)
• Hirschsprung associated GDNF mutations do not prevent RET activation (PMID:11973622)
• the G691S and S904S variants of RET may somehow play a role on the age of onset of MEN 2A (PMID:11979448)
• Activation of RET tyrosine kinase regulates interleukin-8 production by multiple signaling pathways (PMID:12056817)
• RET activation closely parallels the morphological changes, that it is restricted to those areas of the tumor with the cytological alterations and that it is detectable in both mono- and polyclonal tumors (PMID:12057919)
• RET codon 691 polymorphism is associated with radiation induced tumors with a C-cell hyperplasia of thyroid tumors (PMID:12085189)
• RET/PTC rearrangement in thyroid tumors. Review (PMID:12114746)
• RET expression in papillary thyroid cancer from patients irradiated in childhood for benign conditions. (PMID:12161537)
• Analysis of mutation of protooncogene RET are presented in patients with thyroid medullary carcinoma (PMID:12182057)
• analysis of RET somatic mutations supports the differentiation between sporadic and inherited medullary thyroid carcinoma (PMID:12182058)
• 5’-End RET splicing: absence of variants in normal tissues and intron retention in pheochromocytomas. (PMID:12187076)
• Possible pathogenesis of papillary thyroid carcinoma caused by exon 13 and 14 RET mutations that affect the intracellular domain of ret proto-oncogene protein. (PMID:12193298)
• a protective role of this low-penetrant haplotype in the pathogenesis of HSCR and demonstrate a possible functional effect linked to RET messenger RNA expression. (PMID:12214285)
• genetic interaction between mutations in RET and EDNRB is an underlying mechanism for Hirschsprung disease (PMID:12355085)
• relationship between RET oncogene and Chinese patients with Hirschsprung’s disease (PMID:12439935)
• A novel Val648Ile substitution in RET protooncogene observed in a Cys634Arg multiple endocrine neoplasia type 2A kindred presenting with an adrenocorticotropin-producing pheochromocytoma. (PMID:12466368)
• A founding locus within the RET proto-oncogene may account for a large proportion of apparently sporadic Hirschsprung disease and a subset of cases of sporadic medullary thyroid carcinoma (PMID:12474140)
• Patients with RET codon 790/791 mutations seemed to have a less aggressive clinical course compared with patients with classic multiple endocrine neoplasia type 2A syndrome. (PMID:12490841)
• Amplification and overexpression of mutant RET in multiple endocrine neoplasia type 2-associated medullary thyroid carcinoma. RET germline mutation in codon 634. Tandem duplication.Genomic chromosome 10 abnormalities increase mutant RET mRNA. (PMID:12519890)
• RET proto-oncogene is often stimulated in follicular cell-derived thyroid tumors, not only in papillary carcinoma but also in follicular tumors (follicular adenomas and follicular carcinoma), and may contribute to tumorigenesis of these tumors. (PMID:12608895)
• Not only RET mutations but also RET polymorphic variants may contribute to the occurrence of total intestinal aganglionosis. (PMID:12632375)
• RET/PTC associates with STAT3 and activates it by the specific phosphorylation of the tyrosine 705 residue. STAT3 activation by the RET/PTC tyrosine kinase is one of the critical signaling pathways for the regulation of specific genes. (PMID:12637586)
• High prevalence of BRAF mutations in thyroid cancer is genetic evidence for constitutive activation of the RET/PTC-RAS-BRAF signaling pathway in papillary thyroid carcinoma. (PMID:12670889)
• in RET mutation carriers in Hirschsprung’s disease, the gut caliber change was almost identical to the histologic transition in cases of short segment aganglionosis, whereas these were markedly dissociated in cases exhibiting extensive aganglionosis (PMID:12720173)
• RET rearrangements may not play any distinctive role in driving histotype development and cancer progression in papillary thyroid carcinomas. (PMID:12720532)
• A deletion of the chromosomal region including the RET proto-oncogene is involved in the pathogenesis of SCLC (PMID:12767512)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	ret	ENSDARG00000055305
mus_musculus	Ret	ENSMUSG00000030110
rattus_norvegicus	Ret	ENSRNOG00000014751
drosophila_melanogaster	Ret	FBGN0011829

Paralogs (53): INSRR (ENSG00000027644), MUSK (ENSG00000030304), FLT4 (ENSG00000037280), EPHA3 (ENSG00000044524), ROS1 (ENSG00000047936), LTK (ENSG00000062524), ERBB3 (ENSG00000065361), TIE1 (ENSG00000066056), FGFR2 (ENSG00000066468), FGFR3 (ENSG00000068078), EPHA8 (ENSG00000070886), FGFR1 (ENSG00000077782), EPHA6 (ENSG00000080224), TYRO3 (ENSG00000092445), FLT1 (ENSG00000102755), MET (ENSG00000105976), EPHB6 (ENSG00000106123), PDGFRB (ENSG00000113721), EPHA4 (ENSG00000116106), TEK (ENSG00000120156), FLT3 (ENSG00000122025), KDR (ENSG00000128052), EPHB2 (ENSG00000133216), PDGFRA (ENSG00000134853), EPHA7 (ENSG00000135333), IGF1R (ENSG00000140443), NTRK3 (ENSG00000140538), ERBB2 (ENSG00000141736), EPHA2 (ENSG00000142627), EPHA5 (ENSG00000145242), EGFR (ENSG00000146648), EPHA1 (ENSG00000146904), NTRK2 (ENSG00000148053), MERTK (ENSG00000153208), EPHB1 (ENSG00000154928), KIT (ENSG00000157404), FGFR4 (ENSG00000160867), DDR2 (ENSG00000162733), RYK (ENSG00000163785), MST1R (ENSG00000164078)

Protein

Protein identifiers

Proto-oncogene tyrosine-protein kinase receptor Ret — P07949 (reviewed: P07949)

Alternative names: Cadherin family member 12, Proto-oncogene c-Ret

All UniProt accessions (10): A0A087WWB1, A0A1W2PPN7, A0A1W2PSA1, A0A5F9ZHB7, A0A5F9ZHR6, A0A804HIK7, A0A804HL71, A0AAQ5BH28, C9JYL6, P07949

UniProt curated annotations — full annotation on UniProt →

Function. Receptor tyrosine-protein kinase involved in numerous cellular mechanisms including cell proliferation, neuronal navigation, cell migration, and cell differentiation in response to glia cell line-derived growth family factors (GDNF, NRTN, ARTN, PSPN and GDF15). In contrast to most receptor tyrosine kinases, RET requires not only its cognate ligands but also coreceptors, for activation. GDNF ligands (GDNF, NRTN, ARTN, PSPN and GDF15) first bind their corresponding GDNFR coreceptors (GFRA1, GFRA2, GFRA3, GFRA4 and GFRAL, respectively), triggering RET autophosphorylation and activation, leading to activation of downstream signaling pathways, including the MAPK- and AKT-signaling pathways. Acts as a dependence receptor via the GDNF-GFRA1 signaling: in the presence of the ligand GDNF in somatotrophs within pituitary, promotes survival and down regulates growth hormone (GH) production, but triggers apoptosis in absence of GDNF. Required for the molecular mechanisms orchestration during intestine organogenesis via the ARTN-GFRA3 signaling: involved in the development of enteric nervous system and renal organogenesis during embryonic life, and promotes the formation of Peyer’s patch-like structures, a major component of the gut-associated lymphoid tissue. Mediates, through interaction with GDF15-receptor GFRAL, GDF15-induced cell-signaling in the brainstem which triggers an aversive response, characterized by nausea, vomiting, and/or loss of appetite in response to various stresses. Modulates cell adhesion via its cleavage by caspase in sympathetic neurons and mediates cell migration in an integrin (e.g. ITGB1 and ITGB3)-dependent manner. Also active in the absence of ligand, triggering apoptosis through a mechanism that requires receptor intracellular caspase cleavage. Triggers the differentiation of rapidly adapting (RA) mechanoreceptors. Involved in the development of the neural crest. Regulates nociceptor survival and size. Phosphorylates PTK2/FAK1. Isoform 1 in complex with GFRAL induces higher activation of MAPK-signaling pathway than isoform 2 in complex with GFRAL.

Subunit / interactions. Phosphorylated form interacts with the PBT domain of DOK2, DOK4 and DOK5. The phosphorylated form interacts with PLCG1 and GRB7. Interacts (not phosphorylated) with PTK2/FAK1 (via FERM domain). Extracellular cell-membrane anchored RET cadherin fragments form complex in neurons with reduced trophic status, preferentially at the contact sites between somas. Interacts with AIP in the pituitary gland; this interaction prevents the formation of the AIP-survivin complex. Interacts (inactive) with CBLC and CD2AP; dissociates upon activation by GDNF which increases CBLC:CD2AP interaction.

Subcellular location. Cell membrane. Endosome membrane.

Post-translational modifications. Autophosphorylated on C-terminal tyrosine residues upon ligand stimulation. Proteolytically cleaved by caspase-3. The soluble RET kinase fragment is able to induce cell death. The extracellular cell-membrane anchored RET cadherin fragment accelerates cell adhesion in sympathetic neurons.

Disease relevance. Hirschsprung disease 1 (HSCR1) [MIM:142623] A disorder of neural crest development characterized by absence of enteric ganglia along a variable length of the intestine. It is the most common cause of congenital intestinal obstruction. Early symptoms range from complete acute neonatal obstruction, characterized by vomiting, abdominal distention and failure to pass stool, to chronic constipation in the older child. The disease is caused by variants affecting the gene represented in this entry. Medullary thyroid carcinoma (MTC) [MIM:155240] Rare tumor derived from the C cells of the thyroid. Three hereditary forms are known, that are transmitted in an autosomal dominant fashion: (a) multiple neoplasia type 2A (MEN2A), (b) multiple neoplasia type IIB (MEN2B) and (c) familial MTC (FMTC), which occurs in 25-30% of MTC cases and where MTC is the only clinical manifestation. The disease is caused by variants affecting the gene represented in this entry. Multiple neoplasia 2B (MEN2B) [MIM:162300] Uncommon inherited cancer syndrome characterized by predisposition to MTC and phaeochromocytoma which is associated with marfanoid habitus, mucosal neuromas, skeletal and ophthalmic abnormalities, and ganglioneuromas of the intestine tract. Then the disease progresses rapidly with the development of metastatic MTC and a pheochromocytome in 50% of cases. The disease is caused by variants affecting the gene represented in this entry. 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. Multiple neoplasia 2A (MEN2A) [MIM:171400] The most frequent form of medullary thyroid cancer (MTC). It is an inherited cancer syndrome characterized by MTC, phaeochromocytoma and/or hyperparathyroidism. The disease is caused by variants affecting the gene represented in this entry. Various chromosomal aberrations involving RET are known. Some of them have been found in papillary thyroid carcinomas (PTCs). Inversion inv(10)(q11.2;q21) generates the RET/CCDC6 (PTC1) oncogene. Inversion inv(10)(q11.2;q11.2) generates the RET/NCOA4 (PTC3) oncogene. Translocation t(10;14)(q11;q32) with GOLGA5 generates the RET/GOLGA5 (PTC5) oncogene. Translocation t(8;10)(p21.3;q11.2) with PCM1 generates the PCM1/RET fusion. Translocation t(6;10)(p21.3;q11.2) with TRIM27/RFP generates the Delta RFP/RET oncogene. Translocation t(1;10)(p13;q11) with TRIM33 generates the TRIM33/RET (PTC7) oncogene. Translocation t(7;10)(q32;q11) with TRIM24/TIF1 generates the TRIM24/RET (PTC6) oncogene. Translocation t(6;10)(p21.3;q11.2) with TRIM27/RFP generates the TRIM27/RET oncogene. Mutations in RET have been detected in patients with renal agenesis suggesting a possible involvement of this gene in disease pathogenesis.

Activity regulation. Repressed by 4-(3-hydroxyanilino)-quinolines derivatives, indolin-2-one-derivatives, 2-(alkylsulfanyl)-4-(3-thienyl) nicotinonitrile analogs, 3- and 4-substituted beta-carbolin-1-ones, vandetanib, motesanib, sorafenib (BAY 43-9006), cabozantinib (XL184), lenvatinib, sunitinib, nintedanib, and withaferin A (WA). Inactivation by sorafenib both reduces kinase activity and promotes lysosomal degradation.

Induction. Positively regulated by NKX2-1, PHOX2B, SOX10 and PAX3.

Miscellaneous. Treatment with withaferin A (WA) leads tumor regression in medullary thyroid carcinomas (MTC).

Similarity. Belongs to the protein kinase superfamily. Tyr protein kinase family.

Isoforms (2)

UniProt ID	Names	Canonical?
P07949-1	1, RET51	yes
P07949-2	2, RET9

RefSeq proteins (41): NP_001342145, NP_001393672, NP_001393673, NP_001393688, NP_001393689, NP_001393690, NP_001393691, NP_001393692, NP_001393693, NP_001393694, NP_001393695, NP_001393696, NP_001393697, NP_001393698, NP_001393699, NP_001393700, NP_001393701, NP_001393702, NP_001393703, NP_001393704, NP_001393705, NP_001393706, NP_001393707, NP_001393708, NP_001393709, NP_001393710, NP_001393711, NP_001393712, NP_001393713, NP_001393714, NP_001393715, NP_001393716, NP_001393717, NP_001393718, NP_001393719, NP_001393720, NP_001393721, NP_001393722, NP_001393723, NP_065681, NP_066124* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000719	Prot_kinase_dom	Domain
IPR001245	Ser-Thr/Tyr_kinase_cat_dom	Domain
IPR002126	Cadherin-like_dom	Domain
IPR008266	Tyr_kinase_AS	Active_site
IPR011009	Kinase-like_dom_sf	Homologous_superfamily
IPR015919	Cadherin-like_sf	Homologous_superfamily
IPR016249	Tyr_kinase_Ret_rcpt	Family
IPR017441	Protein_kinase_ATP_BS	Binding_site
IPR020635	Tyr_kinase_cat_dom	Domain
IPR040667	Ret_CLD3	Domain
IPR041163	Ret_CLD1	Domain
IPR041317	RET_CLD4	Domain
IPR050122	RTK	Family
IPR055162	RET_CRD	Domain

Pfam: PF00028, PF07714, PF17756, PF17812, PF17813, PF22540

Enzyme classification (BRENDA):

• EC 2.7.10.1 — receptor protein-tyrosine kinase (BRENDA: 44 organisms, 214 substrates, 574 inhibitors, 11 Km, 0 kcat entries)

Substrate kinetics (BRENDA)

4 substrates with measured Km, best-characterized 4. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
ATP	0.0011–0.129	4
AC-DYFE-6-CHLORO-W-NHME	0.0051	1
AC-DYFGW-NHME	0.07	1
YFEW	0.232	1

Catalyzed reactions (Rhea), 1 shown:

• L-tyrosyl-[protein] + ATP = O-phospho-L-tyrosyl-[protein] + ADP + H(+) (RHEA:10596)

UniProt features (296 total): sequence variant 148, strand 26, binding site 24, helix 22, modified residue 13, glycosylation site 13, disulfide bond 13, mutagenesis site 10, turn 5, sequence conflict 4, site 4, chain 3, region of interest 3, topological domain 2, domain 2, signal peptide 1, active site 1, transmembrane region 1, splice variant 1

Structure

Experimental structures (PDB)

34 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
7DUA	X-RAY DIFFRACTION	1.64
4CKJ	X-RAY DIFFRACTION	1.65
6NEC	X-RAY DIFFRACTION	1.87
6I83	X-RAY DIFFRACTION	1.88
7JU5	X-RAY DIFFRACTION	1.9
6NJA	X-RAY DIFFRACTION	1.92
6NE7	X-RAY DIFFRACTION	1.99
2IVS	X-RAY DIFFRACTION	2
2X2L	X-RAY DIFFRACTION	2
2X2U	X-RAY DIFFRACTION	2
6I82	X-RAY DIFFRACTION	2.05
7JU6	X-RAY DIFFRACTION	2.06
4CKI	X-RAY DIFFRACTION	2.12
2IVV	X-RAY DIFFRACTION	2.25
6FEK	X-RAY DIFFRACTION	2.3
6VHG	X-RAY DIFFRACTION	2.3
7DU9	X-RAY DIFFRACTION	2.31
7NZN	X-RAY DIFFRACTION	2.39
2IVU	X-RAY DIFFRACTION	2.5
2X2M	X-RAY DIFFRACTION	2.5
5AMN	X-RAY DIFFRACTION	2.57
2IVT	X-RAY DIFFRACTION	2.6
2X2K	X-RAY DIFFRACTION	2.6
7DU8	X-RAY DIFFRACTION	2.75
5FM3	X-RAY DIFFRACTION	2.95
5FM2	X-RAY DIFFRACTION	3.3
7RUN	X-RAY DIFFRACTION	3.51
6Q2O	ELECTRON MICROSCOPY	3.65
6Q2S	ELECTRON MICROSCOPY	3.8
6Q2J	ELECTRON MICROSCOPY	4.1

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P07949-F1	79.27	0.52

Functional residue map

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

Catalytic / active sites (5): 874 (proton acceptor); 587–588 (breakpoint for translocation to form the trim27/ret oncogene); 707–708 (cleavage; by caspase-3); 712–713 (breakpoint for translocation to form pcm1-ret; ret-ccdc6; ret-golga5; ret-trim24 and ret-trim33 oncogenes); 1017–1018 (cleavage; by caspase-3)

Ligand- & substrate-binding residues (24): 178; 179; 230; 232; 232; 264; 265; 266; 267; 267; 268; 300 …

Post-translational modifications (13): 687, 696, 806, 809, 826, 900, 905, 981, 1015, 1029, 1062, 1090, 1096

Disulfide bonds (13): 137–142, 157–197, 166–243, 426–430, 449–478, 515–531, 519–541, 528–558, 565–581, 570–585, 609–620, 611–618, 630–634

Glycosylation sites (13): 98, 151, 199, 336, 343, 361, 367, 377, 394, 448, 468, 554, 688

Mutagenesis-validated functional residues (10):

Position	Phenotype
36	defects in maturation and processing.
41	defects in maturation and processing.
85	defects in maturation and processing.
707	impaired cleavage by caspase-3 and loss of induced cell death.
708–1114	loss of induced cell death, but increased cell aggregation.
734	enhanced protein autophosphorylation due to enhanced substrate presentation in trans.
758	loss of kinase activity. no effect on interaction with and dissociation from cblc and cd2ap.
912	enhanced protein autophosphorylation due to enhanced substrate presentation in trans.
913	enhanced protein autophosphorylation due to enhanced substrate presentation in trans.
1062	abolishes gfral-mediated mapk1/mapk2 phosphorylation.

Function

Pathways and Gene Ontology

Reactome pathways

5 pathways

ID	Pathway
R-HSA-5673001	RAF/MAP kinase cascade
R-HSA-8853659	RET signaling
R-HSA-9768919	NPAS4 regulates expression of target genes
R-HSA-9830364	Formation of the nephric duct
R-HSA-9830674	Formation of the ureteric bud

MSigDB gene sets: 586 (showing top): GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, TGGTGCT_MIR29A_MIR29B_MIR29C, ELVIDGE_HYPOXIA_DN, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_URETER_DEVELOPMENT, GOBP_METANEPHROS_DEVELOPMENT, E2F4DP1_01, TGCTGCT_MIR15A_MIR16_MIR15B_MIR195_MIR424_MIR497, GOBP_CELLULAR_RESPONSE_TO_LIPID, PEREZ_TP63_TARGETS, GOBP_NEURON_MATURATION, GOZGIT_ESR1_TARGETS_DN, GOBP_POSITIVE_REGULATION_OF_KIDNEY_DEVELOPMENT, GOBP_POSITIVE_REGULATION_OF_MAPK_CASCADE, GOBP_EXTRINSIC_APOPTOTIC_SIGNALING_PATHWAY

GO Biological Process (36): MAPK cascade (GO:0000165), ureteric bud development (GO:0001657), neural crest cell migration (GO:0001755), embryonic epithelial tube formation (GO:0001838), homophilic cell-cell adhesion (GO:0007156), neuron cell-cell adhesion (GO:0007158), signal transduction (GO:0007165), cell surface receptor protein tyrosine kinase signaling pathway (GO:0007169), axon guidance (GO:0007411), posterior midgut development (GO:0007497), positive regulation of gene expression (GO:0010628), positive regulation of neuron projection development (GO:0010976), regulation of cell adhesion (GO:0030155), positive regulation of cell migration (GO:0030335), membrane protein proteolysis (GO:0033619), positive regulation of cell adhesion mediated by integrin (GO:0033630), ureter maturation (GO:0035799), glial cell-derived neurotrophic factor receptor signaling pathway (GO:0035860), neuron maturation (GO:0042551), positive regulation of MAPK cascade (GO:0043410), positive regulation of cell size (GO:0045793), positive regulation of DNA-templated transcription (GO:0045893), response to pain (GO:0048265), enteric nervous system development (GO:0048484), regulation of axonogenesis (GO:0050770), positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction (GO:0051897), Peyer’s patch morphogenesis (GO:0061146), cellular response to retinoic acid (GO:0071300), positive regulation of metanephric glomerulus development (GO:0072300), lymphocyte migration into lymphoid organs (GO:0097021), GDF15-GFRAL signaling pathway (GO:0160144), positive regulation of extrinsic apoptotic signaling pathway in absence of ligand (GO:2001241), protein phosphorylation (GO:0006468), cell adhesion (GO:0007155), nervous system development (GO:0007399), neuron differentiation (GO:0030182)

GO Molecular Function (10): protein tyrosine kinase activity (GO:0004713), transmembrane receptor protein tyrosine kinase activity (GO:0004714), calcium ion binding (GO:0005509), ATP binding (GO:0005524), signaling receptor activity (GO:0038023), nucleotide binding (GO:0000166), protein kinase activity (GO:0004672), protein binding (GO:0005515), kinase activity (GO:0016301), transferase activity (GO:0016740)

GO Cellular Component (7): plasma membrane (GO:0005886), endosome membrane (GO:0010008), axon (GO:0030424), signaling receptor complex (GO:0043235), plasma membrane protein complex (GO:0098797), endosome (GO:0005768), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
Kidney development	2
MAPK1/MAPK3 signaling	1
Axon guidance	1
Transcriptional Regulation by NPAS4	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cell-cell adhesion	2
regulation of cellular process	2
intracellular signaling cassette	1
mesonephric tubule development	1
neural crest cell development	1
mesenchymal cell migration	1
morphogenesis of embryonic epithelium	1
epithelial tube formation	1
cell communication	1
cellular process	1
signaling	1
cellular response to stimulus	1
enzyme-linked receptor protein signaling pathway	1
axonogenesis	1
neuron projection guidance	1
midgut development	1
anatomical structure development	1
gene expression	1
regulation of gene expression	1
positive regulation of macromolecule biosynthetic process	1
regulation of neuron projection development	1
neuron projection development	1
positive regulation of cell projection organization	1
cell adhesion	1
cell migration	1
regulation of cell migration	1
positive regulation of cell motility	1
proteolysis	1
cell adhesion mediated by integrin	1
regulation of cell adhesion mediated by integrin	1
positive regulation of cell adhesion	1
animal organ maturation	1
ureter development	1
cell surface receptor protein tyrosine kinase signaling pathway	1
cell maturation	1
neuron development	1
MAPK cascade	1
regulation of MAPK cascade	1
positive regulation of intracellular signal transduction	1
protein kinase activity	1

Protein interactions and networks

STRING

3778 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
RET	GFRA1	P56159	999
RET	GDNF	P39905	999
RET	NRTN	Q99748	997
RET	ARTN	Q5T4W7	996
RET	PSPN	O60542	994
RET	GFRA3	O60609	994
RET	GFRA2	O00451	994
RET	GFRAL	Q6UXV0	988
RET	NCOA4	Q13772	942
RET	PTCH1	Q13635	915
RET	MPST	P25325	906
RET	SDHD	O14521	904
RET	TMEM127	O75204	903
RET	NCOA4	Q13772	897

IntAct

76 interactions, top by confidence:

A	B	Type	Score
RET	CBL	psi-mi:“MI:0915”(physical association)	0.700
CBL	RET	psi-mi:“MI:0915”(physical association)	0.700
RET	TLN1	psi-mi:“MI:0407”(direct interaction)	0.620
TLN1	RET	psi-mi:“MI:0407”(direct interaction)	0.620
Sh2b1	RET	psi-mi:“MI:0915”(physical association)	0.620
Sh2b1	RET	psi-mi:“MI:0914”(association)	0.620
RET	NOTCH2NLA	psi-mi:“MI:0915”(physical association)	0.560
NOTCH2NLA	RET	psi-mi:“MI:0915”(physical association)	0.560
EGFR	RET	psi-mi:“MI:0915”(physical association)	0.550
RET	EGFR	psi-mi:“MI:0915”(physical association)	0.550
RET	FGFR4	psi-mi:“MI:0915”(physical association)	0.500
RET	ALK	psi-mi:“MI:0915”(physical association)	0.500
PLCG1	RET	psi-mi:“MI:2364”(proximity)	0.480
RET	STAT3	psi-mi:“MI:2364”(proximity)	0.480
STAT3	RET	psi-mi:“MI:0914”(association)	0.480
PLCG1	RET	psi-mi:“MI:0914”(association)	0.480
Plcg1	RET	psi-mi:“MI:0915”(physical association)	0.480
Plcg1	RET	psi-mi:“MI:0914”(association)	0.480
RET	RET	psi-mi:“MI:0407”(direct interaction)	0.440
GAS1	RET	psi-mi:“MI:0407”(direct interaction)	0.440
FAU	RET	psi-mi:“MI:0195”(covalent binding)	0.440

BioGRID (349): NOTCH2NL (Two-hybrid), RET (Reconstituted Complex), AIP (PCA), AIP (Affinity Capture-Western), RET (Affinity Capture-Western), RET (Two-hybrid), RET (Affinity Capture-MS), ZBTB48 (Affinity Capture-MS), RET (Affinity Capture-MS), RET (Affinity Capture-MS), RET (Affinity Capture-MS), RET (Affinity Capture-MS), RET (Affinity Capture-MS), HIST1H3A (Affinity Capture-MS), KYNU (Affinity Capture-MS)

ESM2 similar proteins: A0A1D5NSM8, A1X150, A2AVA0, B1AUH1, B3DK56, B3N666, B4HY03, B4NZY8, B4Q599, E2RK30, G3V9H8, O14522, O73791, O97827, P00545, P05622, P07333, P07949, P08F94, P09581, P09619, P0C6B8, P13369, P14616, P14617, P28827, P28828, P35546, P35822, P35916, P35917, P54758, P79749, Q00495, Q02763, Q05030, Q06805, Q06806, Q06807, Q15262

Diamond homologs: A0JM20, A0M8R7, A0M8S8, A1X150, F1QVU0, G3V9H8, O02466, O35346, P00519, P00520, P00521, P00522, P00529, P06213, P07949, P08069, P08581, P08941, P09760, P0DV84, P10447, P13368, P14617, P16056, P20806, P22182, P23049, P30530, P33497, P34152, P34925, P35546, P35590, P42684, P55144, P55146, P57097, P70451, P97523, P97793

SIGNOR signaling

68 interactions.

A	Effect	B	Mechanism
RET	up-regulates	FRS2	binding
RET	up-regulates	DOK4	binding
RET	up-regulates	DOK5	binding
RET	up-regulates	RET	phosphorylation
RET	up-regulates	DOK6	binding
RET	up-regulates	MAPK1	phosphorylation
RET	up-regulates	MAPK3	phosphorylation
PTPRJ	down-regulates	RET	dephosphorylation
RET	up-regulates	MAPK14	phosphorylation
RET	up-regulates	AKT	phosphorylation
PRKACA	down-regulates	RET	phosphorylation
PTK2	up-regulates	RET	phosphorylation
RET	up-regulates	PTK2	phosphorylation
motesanib	down-regulates	RET	“chemical inhibition”
TG101209	down-regulates	RET	“chemical inhibition”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 57 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
Spry regulation of FGF signaling	6	107.1×	2e-09
Constitutive Signaling by EGFRvIII	6	107.1×	2e-09
GRB2:SOS provides linkage to MAPK signaling for Integrins	5	89.2×	6e-08
Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants	6	85.7×	5e-09
Signaling by ALK	6	85.7×	5e-09
Insulin receptor signalling cascade	5	84.0×	7e-08
Signaling by ERBB2 ECD mutants	5	84.0×	7e-08
Signalling to ERKs	5	75.1×	1e-07

GO biological processes:

GO term	Partners	Fold	FDR
epidermal growth factor receptor signaling pathway	10	51.6×	2e-12
insulin-like growth factor receptor signaling pathway	5	51.6×	1e-05
insulin receptor signaling pathway	6	27.7×	2e-05
regulation of cell population proliferation	5	12.0×	2e-03
positive regulation of ERK1 and ERK2 cascade	5	8.9×	5e-03
ubiquitin-dependent protein catabolic process	5	7.7×	7e-03
cell migration	6	7.7×	3e-03
negative regulation of apoptotic process	8	5.8×	2e-03

Disease & clinical

Cancer significance

From CIViC — curated cancer-variant interpretation:

RET mutations and the RET fusion RET-PTC lead to activation of this tyrosine kinase receptor and are associated with thyroid cancers. RET point mutations are the most common mutations identified in medullary thyroid cancer (MTC) with germline and somatic mutations in RET associated with hereditary and sporadic forms, respectively. The most common somatic form mutation is M918T (exon 16) and a variety of other mutations effecting exons 10, 11 and 15 have been described. The prognostic significance of these mutations have been hotly debated in the field, however, data suggests that some RET mutation may confer drug resistance. Highly selective and well-tolerated RET inhibitors, selpercatinib (LOXO-292) and pralsetinib (BLU-667), have been FDA approved recently for the treatment of RET fusion-positive non-small-cell lung cancer, RET fusion-positive thyroid cancer and RET-mutant medullary thyroid cancer.

From intOGen — cancer-driver classification: activating (oncogene-like) across 6 cancer types — ANGS, MEL, NSCLC, PGNG, SOFT_TISSUE, WDTC.

Clinical variants and AI predictions

ClinVar

4311 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	103
Likely pathogenic	46
Uncertain significance	2046
Likely benign	1346
Benign	101

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1069637	NM_020975.6(RET):c.318G>A (p.Trp106Ter)	Pathogenic
1197458	NM_020975.6(RET):c.2137-1G>A	Pathogenic
1372611	NM_020975.6(RET):c.1826G>C (p.Cys609Ser)	Pathogenic
13905	NM_020975.6(RET):c.1852T>G (p.Cys618Gly)	Pathogenic
13908	NM_020975.6(RET):c.1900T>G (p.Cys634Gly)	Pathogenic
13909	NM_020975.6(RET):c.1901G>A (p.Cys634Tyr)	Pathogenic
13910	NM_020975.6(RET):c.1901G>C (p.Cys634Ser)	Pathogenic
13911	NM_020975.6(RET):c.1901G>T (p.Cys634Phe)	Pathogenic
13913	NM_020975.6(RET):c.1833C>G (p.Cys611Trp)	Pathogenic
13914	NM_020975.6(RET):c.1853G>C (p.Cys618Ser)	Pathogenic
13915	NM_020975.6(RET):c.1858T>C (p.Cys620Arg)	Pathogenic
13916	NM_020975.6(RET):c.1859G>A (p.Cys620Tyr)	Pathogenic
13918	NM_020975.6(RET):c.1902C>G (p.Cys634Trp)	Pathogenic
13925	NM_020975.6(RET):c.538C>T (p.Arg180Ter)	Pathogenic
13928	NM_020975.6(RET):c.1859G>T (p.Cys620Phe)	Pathogenic
13929	NM_020975.6(RET):c.1852T>C (p.Cys618Arg)	Pathogenic
13930	NM_020975.6(RET):c.1892_1903dup (p.Cys634_Arg635insHisGluLeuCys)	Pathogenic
13931	NM_020975.6(RET):c.2304G>C (p.Glu768Asp)	Pathogenic
13933	NM_020975.6(RET):c.1826G>A (p.Cys609Tyr)	Pathogenic
13934	NM_020975.6(RET):c.1860C>G (p.Cys620Trp)	Pathogenic
13941	NM_020975.6(RET):c.1586_1594dup (p.Cys531_Gly532insGluGluCys)	Pathogenic
13942	NM_020975.6(RET):c.1919C>G (p.Ala640Gly)	Pathogenic
13943	NM_020975.6(RET):c.1859G>C (p.Cys620Ser)	Pathogenic
13944	NM_020975.6(RET):c.1825T>C (p.Cys609Arg)	Pathogenic
13946	NM_020975.6(RET):c.2410G>T (p.Val804Leu)	Pathogenic
13950	NM_020975.6(RET):c.1597G>T (p.Gly533Cys)	Pathogenic
13951	NM_020975.6(RET):c.2671T>G (p.Ser891Ala)	Pathogenic
1403312	NM_020975.6(RET):c.1252C>T (p.Arg418Ter)	Pathogenic
1405715	NM_020975.6(RET):c.317G>A (p.Trp106Ter)	Pathogenic
1406541	NM_020975.6(RET):c.2427C>A (p.Tyr809Ter)	Pathogenic

SpliceAI

3595 predictions. Top by Δscore:

Variant	Effect	Δscore
10:43077329:AAGG:A	donor_loss	1.0000
10:43077331:GGT:G	donor_loss	1.0000
10:43100457:A:AG	acceptor_gain	1.0000
10:43100458:G:GG	acceptor_gain	1.0000
10:43100653:G:GT	donor_gain	1.0000
10:43100710:C:G	donor_gain	1.0000
10:43100720:GCA:G	donor_gain	1.0000
10:43100723:G:GG	donor_gain	1.0000
10:43100728:G:GT	donor_gain	1.0000
10:43102628:GG:G	donor_gain	1.0000
10:43102629:GG:G	donor_gain	1.0000
10:43105187:G:GT	donor_gain	1.0000
10:43105191:G:GT	donor_gain	1.0000
10:43106543:C:G	donor_gain	1.0000
10:43106572:G:GG	donor_gain	1.0000
10:43109025:CTGCA:C	acceptor_loss	1.0000
10:43109026:TGCA:T	acceptor_loss	1.0000
10:43109027:GCAGG:G	acceptor_loss	1.0000
10:43109028:CAGG:C	acceptor_loss	1.0000
10:43109029:A:AG	acceptor_gain	1.0000
10:43109029:AG:A	acceptor_gain	1.0000
10:43109029:AGG:A	acceptor_gain	1.0000
10:43109029:AGGGC:A	acceptor_loss	1.0000
10:43109030:G:C	acceptor_loss	1.0000
10:43109030:G:GA	acceptor_gain	1.0000
10:43109030:GG:G	acceptor_gain	1.0000
10:43109030:GGG:G	acceptor_gain	1.0000
10:43109030:GGGC:G	acceptor_gain	1.0000
10:43109030:GGGCT:G	acceptor_gain	1.0000
10:43109231:G:GA	donor_loss	1.0000

AlphaMissense

7243 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
10:43116650:T:C	F735L	0.999
10:43116652:T:A	F735L	0.999
10:43116652:T:G	F735L	0.999
10:43121964:T:A	W917R	0.999
10:43121964:T:C	W917R	0.999
10:43112205:G:C	W543C	0.998
10:43112205:G:T	W543C	0.998
10:43121966:G:C	W917C	0.998
10:43121966:G:T	W917C	0.998
10:43120094:A:C	D874A	0.997
10:43120106:G:T	R878I	0.997
10:43124905:T:A	W988R	0.997
10:43124905:T:C	W988R	0.997
10:43119719:G:T	G861W	0.996
10:43120094:A:T	D874V	0.996
10:43120109:A:T	N879I	0.996
10:43120110:C:A	N879K	0.996
10:43120110:C:G	N879K	0.996
10:43123672:T:A	W935R	0.996
10:43123672:T:C	W935R	0.996
10:43123688:T:C	L940P	0.996
10:43123693:T:A	W942R	0.996
10:43123693:T:C	W942R	0.996
10:43123697:A:T	E943V	0.996
10:43124907:G:C	W988C	0.996
10:43124907:G:T	W988C	0.996
10:43116721:G:C	K758N	0.995
10:43116721:G:T	K758N	0.995
10:43120148:A:T	D892V	0.995
10:43120150:T:C	F893L	0.995

dbSNP variants (sampled 300 via entrez): RS1000022963 (10:43089131 A>G), RS1000067283 (10:43089669 C>T), RS1000133958 (10:43090940 A>G), RS1000183633 (10:43095370 T>C), RS1000202095 (10:43110044 G>A), RS1000282002 (10:43097838 AACTGCTGCTGCAGGCCCC>A), RS1000309719 (10:43115679 C>A,G,T), RS1000340514 (10:43115450 C>A,G,T), RS1000402263 (10:43089471 C>T), RS1000667184 (10:43100782 C>A,G,T), RS1000673492 (10:43116526 C>A,G,T), RS1000762071 (10:43079400 C>T), RS1000764661 (10:43078812 G>A,C), RS1000820130 (10:43105312 T>C), RS1001031443 (10:43099749 A>G)

Disease associations

OMIM: gene MIM:164761 | disease phenotypes: MIM:142623, MIM:155240, MIM:162300, MIM:171300, MIM:171400, MIM:167000, MIM:131100, MIM:191830, MIM:209880, MIM:187500, MIM:114550, MIM:114480, MIM:604370, MIM:155255, MIM:610805, MIM:114500

GenCC curated gene-disease

Disease	Classification	Inheritance
multiple endocrine neoplasia type 2B	Definitive	Autosomal dominant
multiple endocrine neoplasia type 2A	Definitive	Autosomal dominant
familial medullary thyroid carcinoma	Definitive	Autosomal dominant
pheochromocytoma	Definitive	Autosomal dominant
Hirschsprung disease, susceptibility to, 1	Strong	Autosomal dominant
bilateral renal agenesis	Supportive	Autosomal recessive
Hirschsprung disease	Supportive	Autosomal dominant
renal agenesis, unilateral	Supportive	Autosomal dominant
Haddad syndrome	Supportive	Autosomal dominant
renal agenesis	Limited	Autosomal recessive

ClinGen Gene-Disease Validity (2)

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

Disease	Classification	Inheritance
multiple endocrine neoplasia type 2B	Definitive	AD
multiple endocrine neoplasia type 2A	Definitive	AD

Mondo (39): hereditary neoplastic syndrome (MONDO:0015356), multiple endocrine neoplasia type 2 (MONDO:0019003), Hirschsprung disease, susceptibility to, 1 (MONDO:0007723), familial medullary thyroid carcinoma (MONDO:0007958), multiple endocrine neoplasia type 2B (MONDO:0008082), pheochromocytoma (MONDO:0008233), multiple endocrine neoplasia type 2A (MONDO:0008234), ovarian cancer (MONDO:0008170), breast carcinoma (MONDO:0004989), multiple endocrine neoplasia (MONDO:0017169), renal hypodysplasia/aplasia 1 (MONDO:0024519), Hirschsprung disease (MONDO:0018309), pilocytic astrocytoma (MONDO:0016691), central hypoventilation syndrome, congenital (MONDO:0800031), thyroid gland carcinoma (MONDO:0015075)

Orphanet (24): Inherited cancer-predisposing syndrome (Orphanet:140162), Multiple endocrine neoplasia type 2 (Orphanet:653), Multiple endocrine neoplasia type 2A (Orphanet:247698), Multiple endocrine neoplasia type 2B (Orphanet:247709), Hereditary pheochromocytoma-paraganglioma (Orphanet:29072), Hirschsprung disease (Orphanet:388), Isolated familial medullary thyroid carcinoma (Orphanet:99361), Rare ovarian cancer (Orphanet:213500), Multiple endocrine neoplasia (Orphanet:276161), Renal agenesis (Orphanet:411709), Pilocytic astrocytoma (Orphanet:251612), Congenital central hypoventilation syndrome (Orphanet:661), Haddad syndrome (Orphanet:99803), Rare thyroid carcinoma (Orphanet:100088), Medullary thyroid carcinoma (Orphanet:1332)

HPO phenotypes

136 total (30 of 136 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000008	Abnormal morphology of female internal genitalia
HP:0000093	Proteinuria
HP:0000096	Glomerular sclerosis
HP:0000104	Renal agenesis
HP:0000175	Cleft palate
HP:0000179	Thick lower lip vermilion
HP:0000218	High palate
HP:0000286	Epicanthus
HP:0000316	Hypertelorism
HP:0000369	Low-set ears
HP:0000405	Conductive hearing impairment
HP:0000407	Sensorineural hearing impairment
HP:0000457	Depressed nasal ridge
HP:0000486	Strabismus
HP:0000519	Developmental cataract
HP:0000526	Aniridia
HP:0000574	Thick eyebrow
HP:0000740	Episodic paroxysmal anxiety
HP:0000767	Pectus excavatum
HP:0000790	Hematuria
HP:0000822	Hypertension
HP:0000843	Hyperparathyroidism
HP:0000875	Episodic hypertension
HP:0000957	Cafe-au-lait spot
HP:0000975	Hyperhidrosis
HP:0000980	Pallor
HP:0001028	Hemangioma
HP:0001069	Episodic hyperhidrosis
HP:0001095	Hypertensive retinopathy

GWAS associations

14 associations (top):

Study	Trait	p-value
GCST000334_2	Hirschsprung disease	4.000000e-18
GCST002658_5	Hirschsprung disease	6.000000e-19
GCST003465_23	Cannabis dependence symptom count	1.000000e-06
GCST003764_1	Hirschsprung disease	1.000000e-28
GCST003764_3	Hirschsprung disease	4.000000e-43
GCST003764_7	Hirschsprung disease	4.000000e-14
GCST005289_3	Hirschsprung disease	5.000000e-10
GCST005289_4	Hirschsprung disease	2.000000e-101
GCST005289_5	Hirschsprung disease	3.000000e-15
GCST005289_7	Hirschsprung disease	6.000000e-07
GCST006271_1	Hirschsprung disease	3.000000e-21
GCST006585_2154	Blood protein levels	4.000000e-56
GCST009405_2	Smoking behaviour (cigarettes smoked per day)	4.000000e-08
GCST009407_2	Smoking behaviour (cigarettes smoked per day)	3.000000e-07

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0008457	cannabis dependence measurement
EFO:0006525	cigarettes per day measurement

MeSH disease descriptors (20)

Descriptor	Name	Tree numbers
D001064	Appendicitis	C01.463.099; C06.405.205.099; C06.405.469.110.207
D006528	Carcinoma, Hepatocellular	C04.557.470.200.025.255; C04.588.274.623.160; C06.301.623.160; C06.552.697.160
D003248	Constipation	C23.888.821.150
D004806	Ependymoma	C04.557.465.625.600.380.290; C04.557.470.670.380.290; C04.557.580.625.600.380.290
D019214	Gingival Overgrowth	C07.465.714.258.428
D006627	Hirschsprung Disease	C06.198.439; C06.405.469.158.701.439; C16.131.314.439
D007037	Hypothyroidism	C19.874.482
D008527	Medulloblastoma	C04.557.465.625.600.380.515; C04.557.465.625.600.590.500; C04.557.470.670.380.515; C04.557.470.670.590.500; C04.557.580.625.600.380.515; C04.557.580.625.600.590.500
D008531	Megacolon	C06.405.469.158.701
D008831	Microcephaly	C05.660.207.620; C10.500.507.400.500; C16.131.621.207.620; C16.131.666.507.400.500
D009377	Multiple Endocrine Neoplasia	C04.588.322.400; C04.651.600; C04.700.630; C16.320.700.630; C19.344.400
D018813	Multiple Endocrine Neoplasia Type 2a	C04.588.322.400.505; C04.651.600.505; C04.700.630.505; C16.320.700.630.505; C19.344.400.505
D018814	Multiple Endocrine Neoplasia Type 2b	C04.588.322.400.510; C04.651.600.510; C04.700.630.510; C16.320.700.630.510; C19.344.400.510
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
D013771	Tetralogy of Fallot	C14.240.400.849; C14.280.400.849; C16.131.240.400.849
C562840	Breast Cancer, Familial (supp.)
C566906	Cakut (supp.)
C536911	Familial medullary thyroid carcinoma (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (7): CHEMBL2041 (SINGLE PROTEIN), CHEMBL3430877 (CHIMERIC PROTEIN), CHEMBL3430888 (CHIMERIC PROTEIN), CHEMBL3430904 (CHIMERIC PROTEIN), CHEMBL4523602 (CHIMERIC PROTEIN), CHEMBL6195572 (PROTEIN-PROTEIN INTERACTION), CHEMBL6195575 (PROTEIN-PROTEIN INTERACTION)

Molecules with ChEMBL bioactivity

135 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 288,137 (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
CHEMBL1171837	PONATINIB	4	8,955
CHEMBL1173655	AFATINIB	4	15,144
CHEMBL1229517	VEMURAFENIB	4	15,704
CHEMBL1287853	FEDRATINIB	4	3,554
CHEMBL1289494	TIVOZANIB	4	4,455
CHEMBL1289601	LENVATINIB	4	8,784
CHEMBL1289926	AXITINIB	4	15,732
CHEMBL1336	SORAFENIB	4	86,060
CHEMBL1421	DASATINIB ANHYDROUS	4	55,003
CHEMBL1738797	ALECTINIB	4	6,731
CHEMBL1789941	RUXOLITINIB	4	11,547
CHEMBL1834657	INFIGRATINIB PHOSPHATE	4	285
CHEMBL1852688	INFIGRATINIB	4	2,209
CHEMBL1873475	IBRUTINIB	4	7,994
CHEMBL189963	PALBOCICLIB	4	13,102
CHEMBL1946170	REGORAFENIB	4	12,678
CHEMBL1983268	ENTRECTINIB	4	3,510
CHEMBL2103743	TOFACITINIB CITRATE	4	1,672
CHEMBL2103830	FOSTAMATINIB	4	3,841
CHEMBL2105717	CABOZANTINIB	4	11,177
CHEMBL2105759	BARICITINIB	4
CHEMBL221959	TOFACITINIB	4
CHEMBL2325741	CAPIVASERTIB	4
CHEMBL2403108	CERITINIB	4
CHEMBL24828	VANDETANIB	4
CHEMBL255863	NILOTINIB	4
CHEMBL288441	BOSUTINIB	4
CHEMBL3301622	GILTERITINIB	4
CHEMBL3545311	BRIGATINIB	4
CHEMBL3622821	UPADACITINIB	4

Clinical evidence (CIViC)

Drug × variant × indication: 29 predictive associations from 35 curated evidence items; also 7 oncogenic, 3 predisposing, 3 prognostic, 1 functional, 1 diagnostic.

Variant	Therapy	Indication	Effect	Level	CIViC
RET Mutation	Selpercatinib	Medullary Thyroid Carcinoma	Sensitivity/Response	CIViC A	EID12157 +2
RET Fusion OR RET Mutation	Selpercatinib	Solid Tumor	Sensitivity/Response	CIViC A	EID12056 +1
RET Fusion OR RET Mutation	Pralsetinib	Thyroid Cancer	Sensitivity/Response	CIViC A	EID11267
RET M918T	Selpercatinib	Medullary Thyroid Carcinoma	Sensitivity/Response	CIViC A	EID12598
RET E632_L633del	Selpercatinib	Medullary Thyroid Carcinoma	Sensitivity/Response	CIViC B	EID11875 +2
RET M918T	Sorafenib	Medullary Thyroid Carcinoma	Sensitivity/Response	CIViC B	EID1365
RET M918T	Cabozantinib	Medullary Thyroid Carcinoma	Sensitivity/Response	CIViC B	EID7710
RET Mutation	Cabozantinib	Medullary Thyroid Carcinoma	Sensitivity/Response	CIViC B	EID8984
RET V804M	Selpercatinib	Medullary Thyroid Carcinoma	Sensitivity/Response	CIViC C	EID6951 +1
RET M918T AND RET V804M	Selpercatinib	Medullary Thyroid Carcinoma	Sensitivity/Response	CIViC C	EID6950
RET Overexpression	Sunitinib	Papillary Adenocarcinoma	Sensitivity/Response	CIViC C	EID1518
KIF5B::RET Fusion AND ( RET G810C OR RET G810S OR RET G810R )	Selpercatinib	Lung Non-small Cell Carcinoma	Resistance	CIViC C	EID8195
RET M918T AND RET G810S	Selpercatinib	Medullary Thyroid Carcinoma	Resistance	CIViC C	EID8196
RET C618R	Selpercatinib	Cancer	Sensitivity/Response	CIViC D	EID11877
RET C634W	Regorafenib Anhydrous	Gastrointestinal Stromal Tumor	Sensitivity/Response	CIViC D	EID3695
RET E632_L633del	Selpercatinib	Cancer	Sensitivity/Response	CIViC D	EID12712
RET E632_L633del	Pralsetinib	Cancer	Sensitivity/Response	CIViC D	EID12815
RET M918T	Pralsetinib + Selpercatinib	Cancer	Sensitivity/Response	CIViC D	EID11867
RET M918T	Selpercatinib	Cancer	Sensitivity/Response	CIViC D	EID11876
RET M918T	JAK2 Inhibitor AZD1480	Medullary Thyroid Carcinoma	Sensitivity/Response	CIViC D	EID77
RET Mutation	NVP-AST487 + Sapanisertib	Thyroid Gland Carcinoma	Sensitivity/Response	CIViC D	EID4854
RET Overexpression	Vandetanib	Estrogen-receptor Negative Breast Cancer	Sensitivity/Response	CIViC D	EID2992
RET Overexpression	Vandetanib	Breast Cancer	Sensitivity/Response	CIViC D	EID740
RET C634W	Axitinib	Medullary Thyroid Carcinoma	Resistance	CIViC D	EID3694
RET C634W	Motesanib	Medullary Thyroid Carcinoma	Resistance	CIViC D	EID75
RET E632_L633del	Selpercatinib + Pralsetinib	Cancer	Resistance	CIViC D	EID12715
RET M918T	Axitinib	Medullary Thyroid Carcinoma	Resistance	CIViC D	EID3696
RET M918T	Motesanib	Medullary Thyroid Carcinoma	Resistance	CIViC D	EID76
RET V804M	Dasatinib	Chronic Myeloid Leukemia	Resistance	CIViC D	EID7516

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

PharmGKB variants

3 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs1799939	RET		0.00	0
rs77709286	RET		0.00	0
rs74799832	RET		0.00	0

GtoPdb / IUPHAR curated pharmacology

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

Target class: catalytic receptor — Type XIV RTKs: RET

Most potent curated ligand interactions (28 total), top 25:

Ligand	Action	Affinity	Parameter
APS03118	Inhibition	10.02	pIC50
vepafestinib	Inhibition	9.7	pIC50
compound 8h [PMID: 21561767]	Inhibition	9.7	pIC50
resencatinib	Inhibition	9.47	pIC50
pralsetinib	Inhibition	9.4	pIC50
soxataltinib	Inhibition	9.4	pIC50
compound 1 [PMID: 34917254]	Inhibition	9.17	pIC50
WF-47-JS03	Inhibition	9.0	pIC50
sunitinib	Inhibition	8.8	pIC50
gilteritinib	Inhibition	8.77	pIC50
zeteletinib	Inhibition	8.34	pIC50
tamatinib	Inhibition	8.3	pIC50
CEP-11981	Inhibition	8.3	pIC50
ponatinib	Inhibition	8.2	pIC50
lunbotinib	Inhibition	8.18	pIC50
KBP-7018	Inhibition	8.12	pIC50
quizartinib	Inhibition	8.0	pKd
cabozantinib	Inhibition	7.96	pIC50
sorafenib	Inhibition	7.9	pIC50
rivoceranib	Inhibition	7.89	pIC50
selpercatinib	Inhibition	7.85	pIC50
compound 1d [PMID: 21493067]	Inhibition	7.72	pIC50
RG-1530	Inhibition	7.66	pKd
tafetinib	Inhibition	7.17	pIC50
vandetanib	Inhibition	7.0	pIC50

Binding affinities (BindingDB)

2613 measured of 2815 human assays (2815 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
4-amino-6-[2-(1-hydroxycyclopentyl)ethynyl]-7-(1-methylcyclopropyl)-N-(5-methyl-1H-pyrazol-3-yl)pyrrolo[2,3-d]pyrimidine-5-carboxamide	IC50	0.04 nM	US-10233189: Fused pyrimidine compound or salt thereof
4-amino-6-(3-hydroxy-3-methylbut-1-ynyl)-7-(1-methylcyclopropyl)-N-(5-methyl-1H-pyrazol-3-yl)pyrrolo[2,3-d]pyrimidine-5-carboxamide	IC50	0.07 nM	US-10233189: Fused pyrimidine compound or salt thereof
4-amino-7-(1-methylcyclopropyl)-N-(5-methylpyrazolidin-3-yl)-6-(2-pyridin-3-ylethynyl)pyrrolo[2,3-d]pyrimidine-5-carboxamide	IC50	0.09 nM	US-10233189: Fused pyrimidine compound or salt thereof
4-amino-7-(1-methylcyclopropyl)-N-(5-methyl-1H-pyrazol-3-yl)-6-(3-morpholin-4-ylprop-1-ynyl)pyrrolo[2,3-d]pyrimidine-5-carboxamide	IC50	0.1 nM	US-10233189: Fused pyrimidine compound or salt thereof
4-amino-6-[3-(1-hydroxycyclobutyl)prop-1-ynyl]-7-(1-methylcyclopropyl)-N-(5-methyl-1H-pyrazol-3-yl)pyrrolo[2,3-d]pyrimidine-5-carboxamide	IC50	0.1 nM	US-10233189: Fused pyrimidine compound or salt thereof
6-(2-methoxyethoxy)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.3.1]heptan-3-yl)pyridin-3-yl)-1H-pyrazolo[3’,4’:3,4]pyrazolo[1,5-a]pyridine (	IC50	0.1 nM	US-12338253: Nitrogen-containing polycyclic fused ring compound, pharmaceutical composition thereof, preparation method therefor and use thereof
6-(3-fluoropropoxy)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.3.1]heptan-3-yl)pyridin-3-yl)-1H-pyrazolo[3’,4’:3,4]pyrazolo[1,5-a]pyridine	IC50	0.1 nM	US-12338253: Nitrogen-containing polycyclic fused ring compound, pharmaceutical composition thereof, preparation method therefor and use thereof
6-(2-(difluoromethoxy)ethoxy)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.3.1]heptan-3-yl)pyridin-3-yl)-1H-pyrazolo[3’,4’:3,4]pyrazolo[1,5-a]pyridine	IC50	0.1 nM	US-12338253: Nitrogen-containing polycyclic fused ring compound, pharmaceutical composition thereof, preparation method therefor and use thereof
6-(2-fluoroethoxy)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.3.1]heptan-3-yl)pyridin-3-yl)-1H-pyrazolo[3’,4’:3,4]pyrazolo[1,5-a]pyridine	IC50	0.1 nM	US-12338253: Nitrogen-containing polycyclic fused ring compound, pharmaceutical composition thereof, preparation method therefor and use thereof
6-(2,2-difluoroethoxy)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.3.1]heptan-3-yl)pyridin-3-yl)-1H-pyrazolo[3’,4’:3,4]pyrazolo[1,5-a]pyridine	IC50	0.1 nM	US-12338253: Nitrogen-containing polycyclic fused ring compound, pharmaceutical composition thereof, preparation method therefor and use thereof
6-(2-fluoroethoxy)-4-(5-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.3.1]heptan-3-yl)pyrazin-2-yl)-1H-pyrazolo[3’,4’:3,4]pyrazolo[1,5-a]pyridine	IC50	0.1 nM	US-12338253: Nitrogen-containing polycyclic fused ring compound, pharmaceutical composition thereof, preparation method therefor and use thereof
(2S)-2-(((4-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.3.1]heptan-3-yl)pyridin-3-yl)-1H-pyrazolo[3’,4’:3,4]pyrazolo[1,5-a]pyridin-6-yl)oxy)methyl)morpholine	IC50	0.1 nM	US-12338253: Nitrogen-containing polycyclic fused ring compound, pharmaceutical composition thereof, preparation method therefor and use thereof
(3-(5-(6-(2-fluoroethoxy)-1H-pyrazolo[3’,4’:3,4]pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-3,6-diazabicyclo[3.3.1]heptan-6-yl)(6-methoxypyridin-3-yl)methanone	IC50	0.1 nM	US-12338253: Nitrogen-containing polycyclic fused ring compound, pharmaceutical composition thereof, preparation method therefor and use thereof
4-amino-6-bromo-7-(1-methylcyclopropyl)-N-(5-methyl-1H-pyrazol-3-yl)pyrrolo[2,3-d]pyrimidine-5-carboxamide	IC50	0.14 nM	US-10233189: Fused pyrimidine compound or salt thereof
N-[(1S)-1-[6-(4-fluoropyrazol-1-yl)-3-pyridinyl]ethyl]-1-methoxy-4-[4-methyl-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]cyclohexane-1-carboxamide	IC50	0.14 nM	US-20250387388: COMPOUND AS TRK INHIBITOR AND/OR RET INHIBITOR AND USE THEREOF
4-amino-N-(5-bromo-1H-pyrazol-3-yl)-1-tert-butylpyrazolo[3,4-d]pyrimidine-3-carboxamide	IC50	0.15 nM	US-10233189: Fused pyrimidine compound or salt thereof
4-amino-N-(5-bromo-1H-pyrazol-3-yl)-7-(1-fluoro-2-methylpropan-2-yl)pyrrolo[2,3-d]pyrimidine-5-carboxamide	IC50	0.15 nM	US-10233189: Fused pyrimidine compound or salt thereof
4-amino-N-(5-bromo-1H-pyrazol-3-yl)-7-(1-methylcyclopropyl)pyrrolo[2,3-d]pyrimidine-5-carboxamide	IC50	0.15 nM	US-10233189: Fused pyrimidine compound or salt thereof
4-amino-7-(1-methylcyclopropyl)-N-(5-methyl-1H-pyrazol-3-yl)-6-[2-(1-methylpyrazol-4-yl)ethynyl]pyrrolo[2,3-d]pyrimidine-5-carboxamide	IC50	0.15 nM	US-10233189: Fused pyrimidine compound or salt thereof
4-amino-7-(1-methylcyclopropyl)-N-(5-methyl-1H-pyrazol-3-yl)-6-[2-(oxan-4-yl)ethynyl]pyrrolo[2,3-d]pyrimidine-5-carboxamide	IC50	0.15 nM	US-10233189: Fused pyrimidine compound or salt thereof
4-amino-N-(5-bromo-1H-pyrazol-3-yl)-7-tert-butylpyrrolo[2,3-d]pyrimidine-5-carboxamide	IC50	0.15 nM	US-10233189: Fused pyrimidine compound or salt thereof
4-amino-1-(2-cyclopropylpropan-2-yl)-N-(5-methyl-1H-pyrazol-3-yl)pyrazolo[3,4-d]pyrimidine-3-carboxamide	IC50	0.16 nM	US-10233189: Fused pyrimidine compound or salt thereof
4-amino-1-(1-methylcyclopropyl)-N-(5-methyl-1H-pyrazol-3-yl)pyrazolo[3,4-d]pyrimidine-3-carboxamide	IC50	0.17 nM	US-10233189: Fused pyrimidine compound or salt thereof
4-amino-7-(1-methylcyclopropyl)-6-[2-(3-methylimidazol-4-yl)ethynyl]-N-(5-methyl-1H-pyrazol-3-yl)pyrrolo[2,3-d]pyrimidine-5-carboxamide	IC50	0.17 nM	US-10233189: Fused pyrimidine compound or salt thereof
4-amino-7-(1-fluoro-2-methylpropan-2-yl)-N-(5-methyl-1H-pyrazol-3-yl)pyrrolo[2,3-d]pyrimidine-5-carboxamide	IC50	0.2 nM	US-10233189: Fused pyrimidine compound or salt thereof
4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.3.1]heptan-3-yl)pyridin-3-yl)-6-propoxy-1H-pyrazolo[3’,4’:3,4]pyrazolo[1,5-a]pyridine	IC50	0.2 nM	US-12338253: Nitrogen-containing polycyclic fused ring compound, pharmaceutical composition thereof, preparation method therefor and use thereof
2-[2-fluoro-4-[7-(1-methylpyrazol-4-yl)imidazo[1,2-b]pyridazin-3-yl]phenyl]-N-[5-(1,1,1-trifluoro-2-methylpropan-2-yl)-1,2-oxazol-3-yl]acetamide	IC50	0.2 nM	US-12365685: Substituted fused aromatic ring derivative, composition and use thereof
4-amino-1-tert-butyl-N-(5-methyl-1H-pyrazol-3-yl)pyrazolo[3,4-d]pyrimidine-3-carboxamide	IC50	0.21 nM	US-10233189: Fused pyrimidine compound or salt thereof
2-[6-[7-(1-methylpyrazol-4-yl)imidazo[1,2-c]pyrimidin-3-yl]-3-pyridinyl]-N-[5-(1,1,1-trifluoro-2-methylpropan-2-yl)-1,2-oxazol-3-yl]acetamide	IC50	0.21 nM	US-12365685: Substituted fused aromatic ring derivative, composition and use thereof
5-[(4-hydroxycyclohexyl)amino]-3-[4-(4-methylpiperazin-1-yl)anilino]-6-propan-2-ylpyrazine-2-carboxamide	IC50	0.23 nM	US-8969336: Diamino heterocyclic carboxamide compound
4-amino-1-[1-(fluoromethyl)cyclopropyl]-N-(5-methyl-1H-pyrazol-3-yl)pyrazolo[3,4-d]pyrimidine-3-carboxamide	IC50	0.23 nM	US-10233189: Fused pyrimidine compound or salt thereof
4-amino-N-(5-bromo-1H-pyrazol-3-yl)-7-propan-2-ylpyrrolo[2,3-d]pyrimidine-5-carboxamide	IC50	0.23 nM	US-10233189: Fused pyrimidine compound or salt thereof
2-[4-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrimidin-3-yl]phenyl]-N-[5-(1,1,1-trifluoro-2-methylpropan-2-yl)-1,2-oxazol-3-yl]acetamide	IC50	0.23 nM	US-12365685: Substituted fused aromatic ring derivative, composition and use thereof
4-amino-7-cyclopentyl-N-(5-methyl-1H-pyrazol-3-yl)pyrrolo[2,3-d]pyrimidine-5-carboxamide	IC50	0.266 nM	US-10233189: Fused pyrimidine compound or salt thereof
4-amino-7-(1-bicyclo[1.1.1]pentanyl)-N-(5-methyl-1H-pyrazol-3-yl)pyrrolo[2,3-d]pyrimidine-5-carboxamide	IC50	0.27 nM	US-10233189: Fused pyrimidine compound or salt thereof
4-amino-N-(5-methyl-1H-pyrazol-3-yl)-1-(2-thiophen-2-ylpropan-2-yl)pyrazolo[3,4-d]pyrimidine-3-carboxamide	IC50	0.279 nM	US-10233189: Fused pyrimidine compound or salt thereof
2-[4-[7-(1-methylpyrazol-4-yl)imidazo[1,2-c]pyrimidin-3-yl]phenyl]-N-[5-(1,1,1-trifluoro-2-methylpropan-2-yl)-1,2-oxazol-3-yl]acetamide	IC50	0.28 nM	US-12365685: Substituted fused aromatic ring derivative, composition and use thereof
3-[3-methoxy-4-(4-methylpiperazin-1-yl)anilino]-5-(oxan-4-ylamino)-6-propan-2-ylpyrazine-2-carboxamide	IC50	0.29 nM	US-8969336: Diamino heterocyclic carboxamide compound
4-amino-1-tert-butyl-N-(5-methyl-1H-pyrazol-3-yl)pyrazolo[3,4-d]pyrimidine-3-carboxamide	IC50	0.29 nM	US-10233189: Fused pyrimidine compound or salt thereof
Ex. Cpd. 59	IC50	0.3 nM	US-10155768: Fused pyrimidine compound or salt thereof
Ex. Cpd. 86	IC50	0.3 nM	US-10155768: Fused pyrimidine compound or salt thereof
Ex. Cpd. 91	IC50	0.3 nM	US-10155768: Fused pyrimidine compound or salt thereof
Ex. Cpd. 95	IC50	0.3 nM	US-10155768: Fused pyrimidine compound or salt thereof
Ex. Cpd. 103	IC50	0.3 nM	US-10155768: Fused pyrimidine compound or salt thereof
Ex. Cpd. 151	IC50	0.3 nM	US-10155768: Fused pyrimidine compound or salt thereof
Ex. Cpd. 152	IC50	0.3 nM	US-10155768: Fused pyrimidine compound or salt thereof
Ex. Cpd. 157	IC50	0.3 nM	US-10155768: Fused pyrimidine compound or salt thereof
Ex. Cpd. 169	IC50	0.3 nM	US-10155768: Fused pyrimidine compound or salt thereof
4-amino-7-tert-butyl-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrrolo[2,3-d]pyrimidine-5-carboxamide	IC50	0.32 nM	US-10233189: Fused pyrimidine compound or salt thereof
4-amino-7-(1-methylcyclobutyl)-N-(5-methyl-1H-pyrazol-3-yl)pyrrolo[2,3-d]pyrimidine-5-carboxamide	IC50	0.337 nM	US-10233189: Fused pyrimidine compound or salt thereof

ChEMBL bioactivities

6100 potent at pChembl≥5 of 6100 total, top 49 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
10.77	IC50	0.017	nM	CHEMBL5962713
10.40	IC50	0.04	nM	CHEMBL4067871
10.40	IC50	0.04	nM	CHEMBL5944764
10.15	IC50	0.07	nM	CHEMBL5916213
10.05	IC50	0.09	nM	CHEMBL5838635
10.00	IC50	0.1	nM	CHEMBL4218013
10.00	IC50	0.1	nM	CHEMBL5619652
10.00	IC50	0.1	nM	CHEMBL5915060
10.00	IC50	0.1	nM	CHEMBL5913548
10.00	IC50	0.1	nM	CHEMBL6034872
10.00	IC50	0.1	nM	CHEMBL5936500
10.00	IC50	0.1	nM	CHEMBL5902423
10.00	IC50	0.1	nM	CHEMBL6035624
10.00	IC50	0.1	nM	CHEMBL5786997
10.00	IC50	0.1	nM	SELPERCATINIB
9.89	IC50	0.13	nM	VANDETANIB
9.85	IC50	0.14	nM	CHEMBL5807109
9.82	IC50	0.15	nM	CHEMBL5909127
9.82	IC50	0.15	nM	CHEMBL5876102
9.82	IC50	0.15	nM	CHEMBL5787119
9.82	IC50	0.15	nM	CHEMBL5753786
9.82	IC50	0.15	nM	CHEMBL5747405
9.82	IC50	0.15	nM	CHEMBL5895474
9.80	IC50	0.16	nM	CHEMBL5949802
9.80	IC50	0.16	nM	CHEMBL5992123
9.77	IC50	0.17	nM	CHEMBL5757468
9.77	IC50	0.17	nM	CHEMBL5747090
9.77	IC50	0.17	nM	CHEMBL5982797
9.75	IC50	0.177	nM	SELPERCATINIB
9.70	IC50	0.2	nM	CHEMBL4062877
9.70	IC50	0.2	nM	CHEMBL4218563
9.70	IC50	0.2	nM	CHEMBL5806749
9.70	IC50	0.2	nM	CHEMBL5799517
9.70	IC50	0.2	nM	CHEMBL5824514
9.70	IC50	0.2	nM	CHEMBL5966131
9.70	IC50	0.2	nM	CHEMBL5823521
9.70	IC50	0.2	nM	CHEMBL5838948
9.70	IC50	0.2	nM	CHEMBL5907426
9.70	IC50	0.2	nM	CHEMBL5977183
9.70	IC50	0.2	nM	CHEMBL5887763
9.70	IC50	0.2	nM	CHEMBL5747869
9.70	IC50	0.2	nM	CHEMBL5856917
9.70	IC50	0.2	nM	CHEMBL5783077
9.70	IC50	0.2	nM	CHEMBL5895415
9.70	IC50	0.2	nM	CHEMBL6036577
9.70	IC50	0.2	nM	CHEMBL5847789
9.70	IC50	0.2	nM	CHEMBL5891634
9.70	IC50	0.2	nM	CHEMBL5944502
9.70	IC50	0.2	nM	CHEMBL5796281

PubChem BioAssay actives

1515 with measured affinity, of 4687 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
4-chloro-2-[5-[[(1R)-2-hydroxy-1-phenylethyl]amino]-3-isoquinolin-6-yl-2-pyridinyl]phenol	1450708: Inhibition of recombinant Ret (unknown origin) using poly (Glu,Tyr) 4:1 as substrate after 60 mins by ELISA	ic50	<0.0001	uM
potassium 3-(4-chlorophenyl)-5-[(4-chlorophenyl)sulfanylmethyl]-1,4-diaza-2-azanidacyclopenta-3,5-diene	1394718: Inhibition of wild type recombinant human RET using peptide as substrate by fluorimetric analysis	ic50	<0.0001	uM
1-[4-(5-ethoxy-6-oxo-1H-pyridin-3-yl)-2-fluorophenyl]-3-[4-[(4-ethylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl]urea	1384880: Inhibition of human RET using cisbio TK biotin-peptide as substrate preincubated for 30 mins followed by substrate addition measured after 1 hr by HTRF assay	ic50	0.0001	uM
4-methyl-N-[3-[(4-methylpiperazin-1-yl)methyl]-5-(trifluoromethyl)phenyl]-3-[2-(6-morpholin-4-ylimidazo[1,2-b]pyridazin-3-yl)ethynyl]benzamide	2130925: Inhibition of human RET kinase-V804M mutant using RRRRRRRRRRRVYSTDYYRLFNPS as substrate in presence of [gamma33P]-ATP and 10 uM ATP by radiometric HotSpot assay	ic50	0.0001	uM
Vandetanib	1895639: Inhibition of RET (unknown origin)	ic50	0.0001	uM
4-fluoro-2-[5-[[(1R)-2-hydroxy-1-phenylethyl]amino]-3-(3-methyl-2H-indazol-5-yl)-2-pyridinyl]phenol	1450708: Inhibition of recombinant Ret (unknown origin) using poly (Glu,Tyr) 4:1 as substrate after 60 mins by ELISA	ic50	0.0002	uM
N-[4-(2-amino-2-methylpropyl)-3-(trifluoromethyl)phenyl]-2-[4-(4-ethoxy-6-oxo-1H-pyridin-3-yl)-2-fluorophenyl]acetamide	1384880: Inhibition of human RET using cisbio TK biotin-peptide as substrate preincubated for 30 mins followed by substrate addition measured after 1 hr by HTRF assay	ic50	0.0002	uM
5-[2-[5-[[4-[[4-(2-hydroxyethyl)piperazin-1-yl]methyl]-3-(trifluoromethyl)phenyl]carbamoyl]-2-methylphenyl]ethynyl]-N,1-dimethylimidazole-2-carboxamide	601224: Inhibition of human RET using KKKSPGEYVNIEFG by Hotspot assay	ic50	0.0002	uM
N-[(1S)-1-[6-(4-fluoropyrazol-1-yl)-3-pyridinyl]ethyl]-1-methoxy-4-[4-methyl-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]cyclohexane-1-carboxamide	1895756: Inhibition of recombinant RET V804L (unknown origin) incubated for 120 mins by Perkin Elmer electrophoretic mobility shift platform method	ic50	0.0003	uM
6-(2-hydroxy-2-methylpropoxy)-4-[6-[(1S,5R)-6-[(6-methoxy-3-pyridinyl)methyl]-3,6-diazabicyclo[3.1.1]heptan-3-yl]-3-pyridinyl]pyrazolo[1,5-a]pyridine-3-carbonitrile	1995913: Binding affinity to RET (unknown origin) assessed as dissociation constant in presence of ATP by FRET based Z’-Lyte assay	kd	0.0003	uM
Ponatinib	1435448: Inhibition of recombinant RET (unknown origin) using poly (Glu,Tyr) 4:1 as substrate after 60 mins by ELISA	ic50	0.0003	uM
1-[3-(6,7-dimethoxyquinazolin-4-yl)oxyphenyl]-3-[5-(1,1,1-trifluoro-2-methylpropan-2-yl)-1,2-oxazol-3-yl]urea	1895750: Inhibition of CCDC6-RET (unknown origin)	ic50	0.0003	uM
Selpercatinib	1895755: Inhibition of wildtype RET (unknown origin) incubated for 120 mins by Perkin Elmer electrophoretic mobility shift platform method	ic50	0.0004	uM
5-fluoro-2-[5-[[(1R)-2-hydroxy-1-phenylethyl]amino]-3-(3-methyl-2H-indazol-5-yl)-2-pyridinyl]phenol	1450708: Inhibition of recombinant Ret (unknown origin) using poly (Glu,Tyr) 4:1 as substrate after 60 mins by ELISA	ic50	0.0004	uM
2-[4-(4-ethoxy-6-oxo-1H-pyridin-3-yl)-2-fluorophenyl]-N-[4-(2-hydroxy-2-methylpropyl)-3-(trifluoromethyl)phenyl]acetamide	1384880: Inhibition of human RET using cisbio TK biotin-peptide as substrate preincubated for 30 mins followed by substrate addition measured after 1 hr by HTRF assay	ic50	0.0004	uM
2-[(1S)-1-[6-(4-fluoropyrazol-1-yl)-3-pyridinyl]ethyl]-9-[4-methyl-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]-2,9-diazaspiro[5.5]undecan-1-one	1776959: Inhibition of RET wild type (unknown origin)	ic50	0.0004	uM
5-[(6,7-dimethoxyquinazolin-4-yl)amino]-2,4-difluorophenol	1283956: Inhibition of human RET cytoplasmic domain (658 to 1114 residues) expressed in baculovirus system preincubated for 15 mins followed by substrate addition measured after 20 mins by HTRF assay	ic50	0.0004	uM
2-[4-(4-ethoxy-6-oxo-1H-pyridin-3-yl)-2-fluorophenyl]-N-[4-(3-hydroxy-2,2-dimethylpropyl)-3-(trifluoromethyl)phenyl]acetamide	1384880: Inhibition of human RET using cisbio TK biotin-peptide as substrate preincubated for 30 mins followed by substrate addition measured after 1 hr by HTRF assay	ic50	0.0004	uM
2-[4-(4-ethoxy-6-oxo-1H-pyridin-3-yl)-2-fluorophenyl]-N-[3-(1,1,1-trifluoro-2-methylpropan-2-yl)-1,2-oxazol-5-yl]acetamide	1384880: Inhibition of human RET using cisbio TK biotin-peptide as substrate preincubated for 30 mins followed by substrate addition measured after 1 hr by HTRF assay	ic50	0.0004	uM
2-[4-(4-ethoxy-6-oxo-1H-pyridin-3-yl)-2-fluorophenyl]-N-[3-(5-methyl-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)phenyl]acetamide	1384880: Inhibition of human RET using cisbio TK biotin-peptide as substrate preincubated for 30 mins followed by substrate addition measured after 1 hr by HTRF assay	ic50	0.0004	uM
2-[4-(4-ethoxy-6-oxo-1H-pyridin-3-yl)-2-fluorophenyl]-N-[5-(1,1,1-trifluoro-2-methylpropan-2-yl)-1,2-oxazol-3-yl]acetamide	1384880: Inhibition of human RET using cisbio TK biotin-peptide as substrate preincubated for 30 mins followed by substrate addition measured after 1 hr by HTRF assay	ic50	0.0004	uM
1-[4-[3-[4-amino-5-(2-fluoro-5-hydroxyphenyl)pyrrolo[2,3-d]pyrimidin-7-yl]cyclobutyl]piperazin-1-yl]ethanone	1774914: Inhibition of RET (658 to 1072) (unknown origin) by HTRF assay	ic50	0.0005	uM
3-[2-(6-chloroimidazo[1,2-b]pyridazin-3-yl)ethynyl]-4-methyl-N-[3-[(4-methylpiperazin-1-yl)methyl]-5-(trifluoromethyl)phenyl]benzamide	2130925: Inhibition of human RET kinase-V804M mutant using RRRRRRRRRRRVYSTDYYRLFNPS as substrate in presence of [gamma33P]-ATP and 10 uM ATP by radiometric HotSpot assay	ic50	0.0005	uM
4-methyl-N-[4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl]-3-[2-[6-[2-(propan-2-ylamino)ethoxy]imidazo[1,2-b]pyridazin-3-yl]ethynyl]benzamide	2130925: Inhibition of human RET kinase-V804M mutant using RRRRRRRRRRRVYSTDYYRLFNPS as substrate in presence of [gamma33P]-ATP and 10 uM ATP by radiometric HotSpot assay	ic50	0.0005	uM
4-methyl-N-[4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl]-3-[2-[6-(2-morpholin-4-ylethoxy)imidazo[1,2-b]pyridazin-3-yl]ethynyl]benzamide	2130925: Inhibition of human RET kinase-V804M mutant using RRRRRRRRRRRVYSTDYYRLFNPS as substrate in presence of [gamma33P]-ATP and 10 uM ATP by radiometric HotSpot assay	ic50	0.0005	uM
(2S,3R,4R,6R)-3-methoxy-2-methyl-4-(methylamino)-29-oxa-1,7,17-triazaoctacyclo[12.12.2.12,6.07,28.08,13.015,19.020,27.021,26]nonacosa-8,10,12,14,19,21,23,25,27-nonaen-16-one	350292: Inhibition of RET	ic50	0.0005	uM
N-[4-(2,2-dimethyl-3-methylsulfonylpropyl)-3-(trifluoromethyl)phenyl]-2-[4-(4-ethoxy-6-oxo-1H-pyridin-3-yl)-2-fluorophenyl]acetamide	1384880: Inhibition of human RET using cisbio TK biotin-peptide as substrate preincubated for 30 mins followed by substrate addition measured after 1 hr by HTRF assay	ic50	0.0006	uM
2-[(1S)-1-[5-(4-fluoropyrazol-1-yl)pyrazin-2-yl]ethyl]-9-[4-methyl-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]-2,9-diazaspiro[5.5]undecan-1-one	1776961: Inhibition of RET M918T mutant (unknown origin)	ic50	0.0006	uM
N-(5-tert-butyl-1,2-oxazol-3-yl)-2-[4-[5-(4-methylsulfonylphenyl)benzimidazol-1-yl]phenyl]acetamide	1561828: Inhibition of RET isoform 9 C634W mutant in human TT cells assessed as reduction in cell proliferation supplemented with fresh medium containing compound for every 2 to 3 days and measured during compound dosing	ic50	0.0007	uM
4-chloro-2-[5-[[(1R)-2-hydroxy-1-phenylethyl]amino]-3-(3-methyl-2H-indazol-5-yl)-2-pyridinyl]phenol	1450708: Inhibition of recombinant Ret (unknown origin) using poly (Glu,Tyr) 4:1 as substrate after 60 mins by ELISA	ic50	0.0007	uM
N-[4-(1-cyanoethyl)-3-(trifluoromethyl)phenyl]-2-[4-(4-ethoxy-6-oxo-1H-pyridin-3-yl)-2-fluorophenyl]acetamide	1384880: Inhibition of human RET using cisbio TK biotin-peptide as substrate preincubated for 30 mins followed by substrate addition measured after 1 hr by HTRF assay	ic50	0.0007	uM
1-[4-[(4-ethylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl]-3-[4-[6-(methylamino)-3-pyridinyl]phenyl]urea	1384880: Inhibition of human RET using cisbio TK biotin-peptide as substrate preincubated for 30 mins followed by substrate addition measured after 1 hr by HTRF assay	ic50	0.0007	uM
1-[4-[3-[4-amino-5-(4-chloro-3-hydroxyphenyl)pyrrolo[2,3-d]pyrimidin-7-yl]cyclobutyl]piperazin-1-yl]ethanone	1774914: Inhibition of RET (658 to 1072) (unknown origin) by HTRF assay	ic50	0.0007	uM
1-N’-[3-fluoro-4-[6-methoxy-7-(3-morpholin-4-ylpropoxy)quinolin-4-yl]oxyphenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide	625121: Binding constant for RET kinase domain	kd	0.0007	uM
N-[4-[(dimethylamino)methyl]-3-(trifluoromethyl)phenyl]-2-[4-(4-ethoxy-6-oxo-1H-pyridin-3-yl)-2-fluorophenyl]acetamide	1384880: Inhibition of human RET using cisbio TK biotin-peptide as substrate preincubated for 30 mins followed by substrate addition measured after 1 hr by HTRF assay	ic50	0.0008	uM
1-[4-[3-[4-amino-5-(3-amino-4-chlorophenyl)pyrrolo[2,3-d]pyrimidin-7-yl]cyclobutyl]piperazin-1-yl]ethanone	1774914: Inhibition of RET (658 to 1072) (unknown origin) by HTRF assay	ic50	0.0008	uM
5-cyano-N-[2-(cyclohexen-1-yl)-4-[1-[2-(dimethylamino)acetyl]piperidin-4-yl]phenyl]-1H-imidazole-2-carboxamide;hydrochloride	625124: Binding constant for RET(V804M) kinase domain	kd	0.0008	uM
3-(2-aminopropan-2-yl)-N-[(2R)-7-[(7-oxo-6,8-dihydro-5H-1,8-naphthyridin-4-yl)oxy]-1,2,3,4-tetrahydronaphthalen-2-yl]-5-(trifluoromethyl)benzamide	586450: Inhibition of RET	ic50	0.0008	uM
5-[(6,7-dimethoxyquinazolin-4-yl)amino]-4-fluoro-2-methylphenol	1283956: Inhibition of human RET cytoplasmic domain (658 to 1114 residues) expressed in baculovirus system preincubated for 15 mins followed by substrate addition measured after 20 mins by HTRF assay	ic50	0.0008	uM
4-[(1S)-1-[6-(4-fluoropyrazol-1-yl)-3-pyridinyl]ethyl]-9-[4-methyl-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]-1-oxa-4,9-diazaspiro[5.5]undecan-5-one	1776961: Inhibition of RET M918T mutant (unknown origin)	ic50	0.0009	uM
2-[(1S)-1-[6-(4-fluoropyrazol-1-yl)-3-pyridinyl]ethyl]-9-[4-methyl-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]-2-azaspiro[5.5]undecan-1-one	1776959: Inhibition of RET wild type (unknown origin)	ic50	0.0009	uM
5-[2-(8-amino-1,7-naphthyridin-5-yl)ethynyl]-N-[4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl]pyridine-3-carboxamide	2091124: Binding affinity to human recombinant RET V804M mutant assessed as dissociation constant	ic50	0.0009	uM
3-[2-[6-(4-methoxyanilino)imidazo[1,2-b]pyridazin-3-yl]ethynyl]-4-methyl-N-[3-[(4-methylpiperazin-1-yl)methyl]-5-(trifluoromethyl)phenyl]benzamide	2130925: Inhibition of human RET kinase-V804M mutant using RRRRRRRRRRRVYSTDYYRLFNPS as substrate in presence of [gamma33P]-ATP and 10 uM ATP by radiometric HotSpot assay	ic50	0.0009	uM
N-(5-tert-butyl-1,2-oxazol-3-yl)-2-[4-[5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]phenyl]acetamide	2091141: Inhibition of RET V804M mutant (unknown origin) by KINOMEscan assay	ic50	0.0010	uM
4-chloro-3-[5-methyl-3-[4-(2-pyrrolidin-1-ylethoxy)anilino]-1,2,4-benzotriazin-7-yl]phenol	1425154: Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.	kd	0.0010	uM
N-(5-tert-butyl-1,2-oxazol-3-yl)-2-[4-[5-(1-methylpyrrol-3-yl)benzimidazol-1-yl]phenyl]acetamide	1322382: Binding affinity to of human partial length RET expressed in bacterial system by active site-directed competition binding assay	kd	0.0010	uM
1-cyclopropyl-3-[5-[6-(morpholin-4-ylmethyl)-1H-benzimidazol-2-yl]-1H-pyrazol-4-yl]urea	412603: Inhibition of Ret	ic50	0.0010	uM
2-[4-(5-thiophen-3-ylbenzimidazol-1-yl)phenyl]-N-[3-(trifluoromethyl)phenyl]acetamide	1937713: Inhibition of RET (unknown origin) by invitro kinase assay	ic50	0.0010	uM
1-cyclopentyl-3-(1H-pyrrolo[2,3-b]pyridin-5-yl)pyrazolo[3,4-d]pyrimidin-4-amine	507036: Inhibition of Ret	ic50	0.0010	uM
Sunitinib	507422: Inhibition of recombinant Ret by radioactive phosphotransfer assay in presence of 10 uM ATP	ic50	0.0010	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Tretinoin	increases expression, increases phosphorylation, increases secretion, increases response to substance, decreases expression (+1 more)	7
Valproic Acid	affects cotreatment, increases expression, affects expression, increases methylation	7
Estradiol	affects cotreatment, decreases expression, increases expression, decreases reaction	5
sodium arsenite	affects methylation, affects cotreatment, decreases expression, increases expression	3
mercuric bromide	decreases expression, affects cotreatment	2
entinostat	increases expression, affects cotreatment	2
ponatinib	decreases activity	2
Resveratrol	affects cotreatment, increases expression, decreases expression	2
Benzo(a)pyrene	increases methylation, affects methylation	2
Nickel	decreases expression	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
Tamoxifen	decreases reaction, affects cotreatment, increases expression, decreases expression	2
p-Chloromercuribenzoic Acid	decreases expression, affects cotreatment	2
Raloxifene Hydrochloride	affects cotreatment, increases expression, decreases expression	2
pralsetinib	decreases phosphorylation	1
methylmercuric chloride	decreases expression	1
propionaldehyde	increases expression	1
bisphenol A	increases expression	1
lead acetate	affects cotreatment, decreases expression	1
terbufos	increases methylation	1
trichostatin A	increases expression	1
afimoxifene	decreases reaction, increases expression	1
11-nor-delta(9)-tetrahydrocannabinol-9-carboxylic acid	affects methylation, increases abundance	1
chromous chloride	affects cotreatment, decreases expression	1
butyraldehyde	increases expression	1
chromic oxide	affects cotreatment, decreases expression	1
benzo(e)pyrene	increases methylation	1
2,3-bis(3’-hydroxybenzyl)butyrolactone	increases expression, affects cotreatment	1
S-(1,2-dichlorovinyl)cysteine	decreases expression, affects cotreatment	1
indeno(1,2,3-cd)pyrene	decreases expression	1

ChEMBL screening assays

1586 unique, capped per target: 1573 binding, 10 functional, 3 admet

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1005547	Binding	Inhibition of Tel-fused RET kinase-mediated mouse BaF3 cell proliferation	Identification of NVP-TAE684, a potent, selective, and efficacious inhibitor of NPM-ALK. — Proc Natl Acad Sci U S A
CHEMBL1963706	Functional	PUBCHEM_BIOASSAY: Navigating the Kinome. (Class of assay: other) Panel member name: RET	PubChem BioAssay data set
CHEMBL4313074	ADMET	Inhibition of human Ret at 1000 nM using poly (Glu, Tyr)4:1 as substrate measured after 60 mins by ELISA relative to control	Discovery and Development of a Series of Pyrazolo[3,4-d]pyridazinone Compounds as the Novel Covalent Fibroblast Growth Factor Receptor Inhibitors by the Rational Drug Design. — J Med Chem

Cellosaurus cell lines

58 cell lines: 38 cancer cell line, 6 induced pluripotent stem cell, 5 transformed cell line, 5 factor-dependent cell line, 3 embryonic stem cell, 1 finite cell line

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

Cellosaurus	Name	Category	Sex
CVCL_1150	CTV-1	Cancer cell line	Male
CVCL_1326	Karpas-45	Cancer cell line	Male
CVCL_1373	LC-2/ad	Cancer cell line	Female
CVCL_1621	OCUB-M	Cancer cell line	Female
CVCL_1774	TT	Cancer cell line	Female
CVCL_2022	DND-41	Cancer cell line	Male
CVCL_4W01	BHP2-7 Pazopanib selected	Cancer cell line	Female
CVCL_6278	BHP 10-3	Cancer cell line	Female
CVCL_6283	BHP 2-7	Cancer cell line	Female
CVCL_6285	BHP 7-13	Cancer cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT02343562	PHASE4	UNKNOWN	Probiotics for Prophylaxis of Postoperative Hirschsprungs Associated Enterocolitis
NCT07186647	PHASE4	COMPLETED	Laparoscopic-Assisted Transanal Pull-Through for Hirschsprung Disease in Pediatric:Short and Intermediate Outcomes of Two Different Techniques
NCT01379898	PHASE4	COMPLETED	Phenoxybenzamine Versus Doxazosin in PCC Patients
NCT01959711	PHASE4	COMPLETED	Randomized Clinical Trial of Posterior Retroperitoneoscopic Adrenalectomy Versus Lateral Laparoscopic Adrenalectomy
NCT05702944	PHASE4	RECRUITING	The Effect and Safety of Omitting Preoperative Alpha-adrenergic Blockade for Normotensive Pheochromocytoma
NCT04904081	PHASE3	UNKNOWN	Feasibility of Use of Indocyanine Green in Pediatric Colorectal Surgery
NCT03660176	PHASE3	UNKNOWN	Effects of Butyrate Enemas on Postoperative Intestinal Mobility Disorders in Hirschsprung’s Disease
NCT01373736	PHASE3	UNKNOWN	123I-MIBG Scintigraphy in Patients Being Evaluated for Neuroendocrine Tumors
NCT07383246	PHASE3	RECRUITING	CTR-FAPI-guided Precision Surgery for Newly Diagnosed MTC
NCT00002641	PHASE3	COMPLETED	Surgery With or Without Chemotherapy in Treating Patients With Soft Tissue Sarcoma
NCT00002764	PHASE3	COMPLETED	Surgery With or Without Combination Chemotherapy in Treating Patients With Lung Metastases From Soft Tissue Sarcoma
NCT00126412	PHASE3	COMPLETED	Meta-Iodobenzylguanidine (123I mIBG) Scintigraphy in Patients Being Evaluated for Phaeochromocytoma or Neuroblastoma
NCT03176693	PHASE3	COMPLETED	Preoperative Alpha Blockade for Pheochromocytoma
NCT00390325	PHASE2	COMPLETED	Sorafenib Tosylate in Treating Patients With Metastatic, Locally Advanced, or Recurrent Medullary Thyroid Cancer
NCT00630838	PHASE2	COMPLETED	Probiotic Prophylaxis of Hirschprung’s Disease Associated Enterocolitis (HAEC)
NCT01736878	PHASE2	WITHDRAWN	Efficacy and Safety Study of Sorafenib to Treat Advanced Medullary Thyroid Carcinoma
NCT04787328	PHASE2	UNKNOWN	A Study of HA121-28 Tablets in Patients With Medullary Thyroid Carcinoma (MTC)
NCT06121271	PHASE2	NOT_YET_RECRUITING	Trial of Lu-177 DOTATATE (Lutathera®) in Unlicensed Indications
NCT00002608	PHASE2	COMPLETED	Combination Chemotherapy and Tamoxifen in Treating Patients With Solid Tumors
NCT00028106	PHASE2	COMPLETED	131MIBG to Treat Malignant Pheochromocytoma
NCT00107289	PHASE2	RECRUITING	Iodine I 131 Metaiodobenzylguanidine in Treating Patients With Recurrent, Progressive, or Refractory Neuroblastoma or Malignant Pheochromocytoma or Paraganglioma
NCT00466856	PHASE2	TERMINATED	Internal Radiation Therapy in Treating Patients With Liver Metastases From Neuroendocrine Tumors
NCT00843037	PHASE2	COMPLETED	Study Of Sunitinib In Patients With Recurrent Paraganglioma/Pheochromocytoma
NCT00874614	PHASE2	UNKNOWN	A Study Evaluating Ultratrace Iobenguane I131 in Patients With Malignant Relapsed/Refractory Pheochromocytoma/Paraganglioma
NCT00923481	PHASE2	COMPLETED	A Broad Multi-histology Phase II Study of the Multi-Kinase Inhibitor R935788 (Fostamatinib Disodium) in Advanced Colorectal, Non-small Cell Lung, Head and Neck Hepatocellular and Renal Cell Carcinomas, and Pheochromocytoma and Thyroid Tumors (Multi-H…
NCT01152827	PHASE2	COMPLETED	RAD001 in Pheochromocytoma or Nonfunctioning Carcinoid
NCT01413503	PHASE2	COMPLETED	A Phase II Study of 131I- Metaiodobenzylguanidine (MIBG) for Treatment of Metastatic or Unresectable Pheochromocytoma and Related Tumors
NCT01635907	PHASE2	COMPLETED	Dovitinib in Neuroendocrine Tumors
NCT01967576	PHASE2	COMPLETED	Phase II Study of Axitinib (AG-013736) With Evaluation of the VEGF-pathway in Metastatic, Recurrent or Primary Unresectable Pheochromocytoma/Paraganglioma
NCT03165721	PHASE2	TERMINATED	A Phase II Trial of the DNA Methyl Transferase Inhibitor, Guadecitabine (SGI-110), in Children and Adults With Wild Type GIST,Pheochromocytoma and Paraganglioma Associated With Succinate Dehydrogenase Deficiency and HLRCC-associated Kidney Cancer
NCT03206060	PHASE2	RECRUITING	Lu-177-DOTATATE (Lutathera) in Therapy of Inoperable Pheochromocytoma/ Paraganglioma
NCT03839498	PHASE2	ACTIVE_NOT_RECRUITING	Study of Axitinib (AG-013736) With Evaluation of the VEGF-pathway in Pheochromocytoma/Paraganglioma
NCT03946527	PHASE2	ACTIVE_NOT_RECRUITING	LAnreotide in Metastatic Pheochromocytoma / PARAganglioma (LAMPARA)
NCT04276597	PHASE2	WITHDRAWN	Phase-II Study of Lu177DOTATOC in Adults With STTR(+)Pulmonary, Pheochromocytoma, Paraganglioma, Unknown Primary, Thymus NETs (PUTNET), or Any Other Non-.GEP-NET.
NCT04320589	PHASE2	COMPLETED	the Effect of Dexmedetomidine and Magnesium Sulfate in Open Resection of Pheochromocytoma
NCT04400474	PHASE2	COMPLETED	Trial of Cabozantinib Plus Atezolizumab in Advanced and Progressive Neoplasms of the Endocrine System. The CABATEN Study
NCT04711135	PHASE2	ACTIVE_NOT_RECRUITING	Study to Evaluate Safety and Dosimetry of Lutathera in Adolescent Patients With GEP-NETs and PPGLs
NCT04924075	PHASE2	RECRUITING	Belzutifan/MK-6482 for the Treatment of Advanced Pheochromocytoma/Paraganglioma (PPGL), Pancreatic Neuroendocrine Tumor (pNET), Von Hippel-Lindau (VHL) Disease-Associated Tumors, Advanced Gastrointestinal Stromal Tumor (wt GIST), or Solid Tumors With HIF-2α Related Genetic Alterations (MK-6482-015)
NCT05133349	PHASE2	UNKNOWN	A Prospective Phase II Efficacy and Safety Study of Anlotinib in Metastatic or Locally Advanced Pheochromocytoma/ Paraganglioma : Open-label Single-arm, Exploratory Trial
NCT05883085	PHASE2	UNKNOWN	A Study on the Safety and Effectiveness of Anlotinib for Neoadjuvant Treatment of PPGL