Target Information
| Target General Infomation | |||||
|---|---|---|---|---|---|
| Target ID |
T66505
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| Former ID |
TTDNS00536
|
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| Target Name |
smoothened receptor
|
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| Gene Name |
SMO
|
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| Synonyms |
Protein Gx; Smoothened homolog; SMO
|
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| Target Type |
Successful
|
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| Disease | Cancer [ICD9: 140-229; ICD10: C00-C96] | ||||
| Metastatic or locally advanced basal cell carcinoma [ICD9: 173; ICD10: C44] | |||||
| Skin cancers [ICD9: 172, 173; ICD10: C43, C44] | |||||
| Solid tumours [ICD9: 140-199, 210-229; ICD10: C00-D48] | |||||
| Function |
G protein-coupled receptor that probably associates with the patched protein (PTCH) to transduce the hedgehog's proteins signal. Binding of sonic hedgehog (SHH) to its receptor patched is thought to prevent normal inhibition by patched of smoothened (SMO). Required for the accumulation of KIF7 and GLI3 in the cilia.
|
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| BioChemical Class |
GPCR frizzled
|
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| Target Validation |
T39010
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| UniProt ID | |||||
| Sequence |
MAAARPARGPELPLLGLLLLLLLGDPGRGAASSGNATGPGPRSAGGSARRSAAVTGPPPP
LSHCGRAAPCEPLRYNVCLGSVLPYGATSTLLAGDSDSQEEAHGKLVLWSGLRNAPRCWA VIQPLLCAVYMPKCENDRVELPSRTLCQATRGPCAIVERERGWPDFLRCTPDRFPEGCTN EVQNIKFNSSGQCEVPLVRTDNPKSWYEDVEGCGIQCQNPLFTEAEHQDMHSYIAAFGAV TGLCTLFTLATFVADWRNSNRYPAVILFYVNACFFVGSIGWLAQFMDGARREIVCRADGT MRLGEPTSNETLSCVIIFVIVYYALMAGVVWFVVLTYAWHTSFKALGTTYQPLSGKTSYF HLLTWSLPFVLTVAILAVAQVDGDSVSGICFVGYKNYRYRAGFVLAPIGLVLIVGGYFLI RGVMTLFSIKSNHPGLLSEKAASKINETMLRLGIFGFLAFGFVLITFSCHFYDFFNQAEW ERSFRDYVLCQANVTIGLPTKQPIPDCEIKNRPSLLVEKINLFAMFGTGIAMSTWVWTKA TLLIWRRTWCRLTGQSDDEPKRIKKSKMIAKAFSKRHELLQNPGQELSFSMHTVSHDGPV AGLAFDLNEPSADVSSAWAQHVTKMVARRGAILPQDISVTPVATPVPPEEQANLWLVEAE ISPELQKRLGRKKKRRKRKKEVCPLAPPPELHPPAPAPSTIPRLPQLPRQKCLVAAGAWG AGDSCRQGAWTLVSNPFCPEPSPPQDPFLPSAPAPVAWAHGRRQGLGPIHSRTNLMDTEL MDADSDF |
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| Structure |
4JKV; 4N4W; 4O9R; 4QIM; 4QIN
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| Drugs and Mode of Action | |||||
| Drug(s) | Vismodegib | Drug Info | Approved | Metastatic or locally advanced basal cell carcinoma | [1], [2] |
| LDE225 | Drug Info | Phase 2 | Skin cancers | [3], [4] | |
| PF-04449913 | Drug Info | Phase 2 | Cancer | [5], [6] | |
| LY2940680 | Drug Info | Phase 1/2 | Cancer | [7] | |
| BMS-833923 | Drug Info | Phase 1b | Cancer | [8], [9] | |
| LEQ-506 | Drug Info | Phase 1 | Cancer | [10] | |
| TAK-441 | Drug Info | Phase 1 | Solid tumours | [11], [12] | |
| Inhibitor | 1-Benzyl-4-(4-phenylpiperazin-1-yl)phthalazine | Drug Info | [13] | ||
| BMS-833923 | Drug Info | [9] | |||
| CYCLOPAMINE | Drug Info | [14] | |||
| LEQ-506 | Drug Info | [15], [16] | |||
| Antagonist | AZD8542 | Drug Info | [17] | ||
| Hedgehog pathway antagonists | Drug Info | [17] | |||
| SMOi2-17 | Drug Info | [17] | |||
| Smoothened receptor antagonist | Drug Info | [17] | |||
| Modulator | LDE225 | Drug Info | [18] | ||
| LY2940680 | Drug Info | [19] | |||
| PF-04449913 | Drug Info | [19] | |||
| TAK-441 | Drug Info | [20] | |||
| Vismodegib | Drug Info | [1] | |||
| Target Expression Profile (TEP) and Drug Resistance Mutation (DRM) | |||||
| TEP | EXP Info | ||||
| DRM | DRM Info | ||||
| Pathways | |||||
| KEGG Pathway | Hedgehog signaling pathway | ||||
| Pathways in cancer | |||||
| Proteoglycans in cancer | |||||
| Basal cell carcinoma | |||||
| PANTHER Pathway | Hedgehog signaling pathway | ||||
| Pathway Interaction Database | Signaling events mediated by the Hedgehog family | ||||
| Hedgehog signaling events mediated by Gli proteins | |||||
| Reactome | Class B/2 (Secretin family receptors) | ||||
| Hedgehog ' | |||||
| off' | |||||
| state | |||||
| Activation of SMO | |||||
| WikiPathways | Hedgehog Signaling Pathway | ||||
| Organogenesis (Part 2 of 3) | |||||
| Induction (Part 1 of 3) | |||||
| Integrated Pancreatic Cancer Pathway | |||||
| GPCR ligand binding | |||||
| GPCRs, Other | |||||
| References | |||||
| REF 1 | Nat Rev Drug Discov. 2013 Feb;12(2):87-90. | ||||
| REF 2 | (http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 6975). | ||||
| REF 3 | ClinicalTrials.gov (NCT02002689) LDE225 for Patients With PTCH1 or SMO Mutated Tumors. U.S. National Institutes of Health. | ||||
| REF 4 | (http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 8199). | ||||
| REF 5 | ClinicalTrials.gov (NCT01841333) PF-04449913 For Patients With Acute Leukemia at High Risk of Relapse After Donor Stem Cell Transplant. U.S. National Institutes of Health. | ||||
| REF 6 | (http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 8201). | ||||
| REF 7 | ClinicalTrials.gov (NCT01722292) A Study of LY2940680 in Small Cell Lung Cancer. U.S. National Institutes of Health. | ||||
| REF 8 | (http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 8202). | ||||
| REF 9 | Clinical pipeline report, company report or official report of Exelixis (2011). | ||||
| REF 10 | ClinicalTrials.gov (NCT01106508) A Dose Finding and Safety Study of Oral LEQ506 in Patients With Advanced Solid Tumors. U.S. National Institutes of Health. | ||||
| REF 11 | ClinicalTrials.gov (NCT01204073) A Study of TAK-441 in Adult Patients With Advanced Nonhematologic Malignancies. U.S. National Institutes of Health. | ||||
| REF 12 | (http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 8200). | ||||
| REF 13 | J Med Chem. 2009 Jul 9;52(13):3954-68.1-amino-4-benzylphthalazines as orally bioavailable smoothened antagonists with antitumor activity. | ||||
| REF 14 | Bioorg Med Chem Lett. 2009 Jan 15;19(2):328-31. Epub 2008 Dec 3.Identification and structure-activity relationships of ortho-biphenyl carboxamides as potent Smoothened antagonists inhibiting the Hedgehog signaling pathway. | ||||
| REF 15 | Discovery of NVP-LEQ506, a second-generation inhibitor of smoothened. ChemMedChem. 2013 Aug;8(8):1261-5. | ||||
| REF 16 | Structural basis for Smoothened receptor modulation and chemoresistance to anticancer drugs. Nat Commun. 2014 Jul 10;5:4355. | ||||
| REF 17 | (http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Target id: 239). | ||||
| REF 18 | Inhibition of Hedgehog signalling by NVP-LDE225 (Erismodegib) interferes with growth and invasion of human renal cell carcinoma cells. Br J Cancer. 2014 Sep 9;111(6):1168-79. | ||||
| REF 19 | Interpreting expression profiles of cancers by genome-wide survey of breadth of expression in normal tissues. Genomics 2005 Aug;86(2):127-41. | ||||
| REF 20 | TAK-441, a novel investigational smoothened antagonist, delays castration-resistant progression in prostate cancer by disrupting paracrine hedgehog signaling. Int J Cancer. 2013 Oct 15;133(8):1955-66. | ||||
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