Target Information

Target General Infomation
Target ID
T66505
Former ID
TTDNS00536
Target Name
smoothened receptor
Gene Name
SMO
Synonyms
Protein Gx; Smoothened homolog; SMO
Target Type
Successful
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.
BioChemical Class
GPCR frizzled
Target Validation
T39010
UniProt ID
Q99835
Sequence
MAAARPARGPELPLLGLLLLLLLGDPGRGAASSGNATGPGPRSAGGSARRSAAVTGPPPP
LSHCGRAAPCEPLRYNVCLGSVLPYGATSTLLAGDSDSQEEAHGKLVLWSGLRNAPRCWA
VIQPLLCAVYMPKCENDRVELPSRTLCQATRGPCAIVERERGWPDFLRCTPDRFPEGCTN
EVQNIKFNSSGQCEVPLVRTDNPKSWYEDVEGCGIQCQNPLFTEAEHQDMHSYIAAFGAV
TGLCTLFTLATFVADWRNSNRYPAVILFYVNACFFVGSIGWLAQFMDGARREIVCRADGT
MRLGEPTSNETLSCVIIFVIVYYALMAGVVWFVVLTYAWHTSFKALGTTYQPLSGKTSYF
HLLTWSLPFVLTVAILAVAQVDGDSVSGICFVGYKNYRYRAGFVLAPIGLVLIVGGYFLI
RGVMTLFSIKSNHPGLLSEKAASKINETMLRLGIFGFLAFGFVLITFSCHFYDFFNQAEW
ERSFRDYVLCQANVTIGLPTKQPIPDCEIKNRPSLLVEKINLFAMFGTGIAMSTWVWTKA
TLLIWRRTWCRLTGQSDDEPKRIKKSKMIAKAFSKRHELLQNPGQELSFSMHTVSHDGPV
AGLAFDLNEPSADVSSAWAQHVTKMVARRGAILPQDISVTPVATPVPPEEQANLWLVEAE
ISPELQKRLGRKKKRRKRKKEVCPLAPPPELHPPAPAPSTIPRLPQLPRQKCLVAAGAWG
AGDSCRQGAWTLVSNPFCPEPSPPQDPFLPSAPAPVAWAHGRRQGLGPIHSRTNLMDTEL
MDADSDF
Structure
4JKV; 4N4W; 4O9R; 4QIM; 4QIN
Drugs and Mode of Action
Drug(s) Vismodegib Drug Info Approved Metastatic or locally advanced basal cell carcinoma [532210], [542006]
LDE225 Drug Info Phase 2 Skin cancers [524554], [542992]
PF-04449913 Drug Info Phase 2 Cancer [524271], [542995]
LY2940680 Drug Info Phase 1/2 Cancer [524113]
BMS-833923 Drug Info Phase 1b Cancer [542996], [550635]
LEQ-506 Drug Info Phase 1 Cancer [523010]
TAK-441 Drug Info Phase 1 Solid tumours [523175], [542994]
Inhibitor 1-Benzyl-4-(4-phenylpiperazin-1-yl)phthalazine Drug Info [530165]
BMS-833923 Drug Info [550635]
CYCLOPAMINE Drug Info [529870]
LEQ-506 Drug Info [532417], [532877]
Antagonist AZD8542 Drug Info [543616]
Hedgehog pathway antagonists Drug Info [543616]
SMOi2-17 Drug Info [543616]
Smoothened receptor antagonist Drug Info [543616]
Modulator LDE225 Drug Info [532909]
LY2940680 Drug Info [1572591]
PF-04449913 Drug Info [1572591]
TAK-441 Drug Info [532297]
Vismodegib Drug Info [532210]
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 &#039
off&#039
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 523010ClinicalTrials.gov (NCT01106508) A Dose Finding and Safety Study of Oral LEQ506 in Patients With Advanced Solid Tumors. U.S. National Institutes of Health.
Ref 523175ClinicalTrials.gov (NCT01204073) A Study of TAK-441 in Adult Patients With Advanced Nonhematologic Malignancies. U.S. National Institutes of Health.
Ref 524113ClinicalTrials.gov (NCT01722292) A Study of LY2940680 in Small Cell Lung Cancer. U.S. National Institutes of Health.
Ref 524271ClinicalTrials.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 524554ClinicalTrials.gov (NCT02002689) LDE225 for Patients With PTCH1 or SMO Mutated Tumors. U.S. National Institutes of Health.
Ref 532210Nat Rev Drug Discov. 2013 Feb;12(2):87-90.
Ref 542006(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 542992(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 542994(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 542995(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 542996(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 550635Clinical pipeline report, company report or official report of Exelixis (2011).
Ref
Ref 529870Bioorg 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 530165J Med Chem. 2009 Jul 9;52(13):3954-68.1-amino-4-benzylphthalazines as orally bioavailable smoothened antagonists with antitumor activity.
Ref 532210Nat Rev Drug Discov. 2013 Feb;12(2):87-90.
Ref 532297TAK-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.
Ref 532417Discovery of NVP-LEQ506, a second-generation inhibitor of smoothened. ChemMedChem. 2013 Aug;8(8):1261-5.
Ref 532877Structural basis for Smoothened receptor modulation and chemoresistance to anticancer drugs. Nat Commun. 2014 Jul 10;5:4355.
Ref 532909Inhibition 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 543616(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 550635Clinical pipeline report, company report or official report of Exelixis (2011).
Ref 1572591Interpreting expression profiles of cancers by genome-wide survey of breadth of expression in normal tissues. Genomics 2005 Aug;86(2):127-41.

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