Reference Detail

Contact

Missing content? – Request curation!

Request curation for specific Genes, variants, or PubMed publications.

Have questions, comments or suggestions? - Let us know!

Email us at : ckbsupport@jax.org

Ref Type Journal Article
PMID (25636740)
Authors Hoch L, Faure H, Roudaut H, Schoenfelder A, Mann A, Girard N, Bihannic L, Ayrault O, Petricci E, Taddei M, Rognan D, Ruat M
Title MRT-92 inhibits Hedgehog signaling by blocking overlapping binding sites in the transmembrane domain of the Smoothened receptor.
Journal FASEB journal : official publication of the Federation of American Societies for Experimental Biology
Vol 29
Issue 5
Date 2015 May
URL
Abstract Text The Smoothened (Smo) receptor, a member of class F G protein-coupled receptors, is the main transducer of the Hedgehog (Hh) signaling pathway implicated in a wide range of developmental and adult processes. Smo is the target of anticancer drugs that bind to a long and narrow cavity in the 7-transmembrane (7TM) domain. X-ray structures of human Smo (hSmo) bound to several ligands have revealed 2 types of 7TM-directed antagonists: those binding mostly to extracellular loops (site 1, e.g., LY2940680) and those penetrating deeply in the 7TM cavity (site 2, e.g., SANT-1). Here we report the development of the acylguanidine MRT-92, which displays subnanomolar antagonist activity against Smo in various Hh cell-based assays. MRT-92 inhibits rodent cerebellar granule cell proliferation induced by Hh pathway activation through pharmacologic (half maximal inhibitory concentration [IC50] = 0.4 nM) or genetic manipulation. Using [(3)H]MRT-92 (Kd = 0.3 nM for hSmo), we created a comprehensive framework for the interaction of small molecule modulators with hSmo and for understanding chemoresistance linked to hSmo mutations. Guided by molecular docking and site-directed mutagenesis data, our work convincingly confirms that MRT-92 simultaneously recognized and occupied both sites 1 and 2. Our data demonstrate the existence of a third type of Smo antagonists, those entirely filling the Smo binding cavity from the upper extracellular part to the lower cytoplasmic-proximal subpocket. Our studies should help design novel potent Smo antagonists and more effective therapeutic strategies for treating Hh-linked cancers and associated chemoresistance.

Filtering

  • Case insensitive filtering will display rows where any text in any cell matches the filter term
  • Simple literal full or partial string matches
  • Separate multiple filter terms with a spaces, order doesn't matter (a b c and c b a are equivalent )
  • Filtering will only apply to rows that are already loaded on the page, filtering has no impact on query parameters
  • Use quotes to match a longer phrase which contains spaces "mtor c1483f"

Sorting

  • Generally, the default sort order for tables is set to be first column ascending, however, specific tables may set a different default sort order.
  • Click on any column header arrows to sort by that column
  • Hold down the Shift key and click multiple columns to sort by more than one column, be sure to set ascending or descending order for a given column, before moving on to the next column.

Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
MRT-92 MRT-92 8 0
Drug Name Trade Name Synonyms Drug Classes Drug Description
MRT-92 SMO Inhibitor 16 MRT-92 binds to and inhibits Smoothened (SMO), resulting in decreased Hedgehog (Hh) pathway signaling and reduced tumor cell proliferation (PMID: 25636740).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
SMO D384A missense unknown SMO D384A lies within the type-I drug-binding site of the Smo protein (PMID: 25636740). D384A has been demonstrated to confer resistance due to reduced Smo inhibitor binding (PMID: 25636740), but has not been biochemically characterized and therefore, its effect on Smo protein function is unknown (PubMed, Apr 2020). Y
SMO I408F missense unknown SMO I408F lies within transmembrane domain 5 of the Smo protein (UniProt.org). I408F has been identified in the scientific literature (PMID: 25636740, PMID: 25008467), but has not been biochemically characterized and therefore, its effect on Smo protein function is unknown (PubMed, Apr 2020).
SMO L325F missense unknown SMO L325F lies within transmembrane domain 3 of the Smo protein (UniProt.org). L325F has been demonstrated to confer resistance due to reduced Smo inhibitor binding (PMID: 25636740), but has not been biochemically characterized and therefore, its effect on Smo protein function is unknown (PubMed, Apr 2020). Y
SMO M525G missense unknown SMO M525G lies within transmembrane domain 7 of the Smo protein (UniProt.org). M525G has been demonstrated to confer resistance due to reduced Smo inhibitor binding (PMID: 25636740), but has not been biochemically characterized and therefore, its effect on Smo protein function is unknown (PubMed, Apr 2020). Y
SMO R400A missense unknown SMO R400A lies within the type-I drug-binding site of the Smo protein (PMID: 25636740). R400A has been demonstrated to confer resistance due to reduced Smo inhibitor binding (PMID: 25636740), but has not been biochemically characterized and therefore, its effect on Smo protein function is unknown (PubMed, Apr 2020). Y
SMO S387A missense unknown SMO S387A lies within the type-I drug-binding site of the Smo protein (PMID: 25636740). S387A results in altered cellular localization as demonstrated by increased Smo protein in cell membranes as compared to wild-type in culture (PMID: 25636740), but has not been fully characterized and therefore, its effect on Smo protein function is unknown (PubMed, Apr 2020).
SMO S387N missense unknown SMO S387N lies within the type-I drug-binding site of the Smo protein (PMID: 25636740, PMID: 25759019). S387N has been demonstrated to confer resistance to Hh pathway inhibitors (PMID: 25759019), but has not been biochemically characterized and therefore, its effect on Smo protein function is unknown (PubMed, Apr 2020). Y
SMO T466F missense unknown SMO T466F lies within transmembrane domain 6 of the Smo protein (UniProt.org). T466F results in reduced binding to Smo inhibitors as compared to wild-type Smo (PMID: 25636740), but has not been biochemically characterized and therefore, its effect on Smo protein function is unknown (PubMed, Apr 2020).
SMO V329F missense loss of function - predicted SMO V329F lies within transmembrane domain 3 of the Smo protein (UniProt.org). V329F (corresponds to V333F in mouse) results in reduced expression of Gli1 protein and mRNA in cell culture (PMID: 27437577), and demonstrates reduced binding to Smo inhibitors (PMID: 25636740, PMID: 25008467). Y
SMO Y394A missense unknown SMO Y394A lies within the type-I drug-binding site of the Smo protein (PMID: 25636740). Y394A has been demonstrated to confer resistance due to reduced Smo inhibitor binding (PMID: 25636740), but has not been biochemically characterized and therefore, its effect on Smo protein function is unknown (PubMed, Apr 2020). Y
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
SMO Y394A Advanced Solid Tumor predicted - resistant MRT-92 Preclinical Actionable In a preclinical study, transformed human cells expressing SMO Y394A displayed reduced binding to MRT-92 (PMID: 25636740). 25636740
SMO R400A Advanced Solid Tumor predicted - sensitive MRT-92 Preclinical Actionable In a preclincal, transformed human cells expressing SMO R400A displayed reduced binding to MRT-92 (PMID: 25636740). 25636740
SMO V329F Advanced Solid Tumor predicted - resistant MRT-92 Preclinical Actionable In a preclinical study, transformed human cells expressing SMO V329F displayed reduced binding to MRT-92 (PMID: 25636740). 25636740
SMO T466F Advanced Solid Tumor predicted - resistant MRT-92 Preclinical Actionable In a preclinical study, transformed human cells expressing SMO T466F displayed reduced binding to MRT-92 (PMID: 25636740). 25636740
SMO E518K Advanced Solid Tumor predicted - resistant MRT-92 Preclinical Actionable In a preclinical study, transformed human cells expressing SMO E518K displayed reduced binding to MRT-92 (PMID: 25636740). 25636740
SMO D384A Advanced Solid Tumor predicted - resistant MRT-92 Preclinical Actionable In a preclinical study, transformed human cells expressing SMO D384A displayed reduced binding to MRT-92 (PMID: 25636740). 25636740
SMO L325F Advanced Solid Tumor predicted - resistant MRT-92 Preclinical Actionable In a preclinical study, transformed human cells expressing SMO L325F displayed reduced binding to MRT-92 (PMID: 25636740). 25636740
SMO M525G Advanced Solid Tumor predicted - resistant MRT-92 Preclinical Actionable In a preclinical study, transformed human cells expressing SMO M525G displayed reduced binding to MRT-92 (PMID: 25636740). 25636740