2015
DOI: 10.1096/fj.14-267849
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MRT‐92 inhibits Hedgehog signaling by blocking overlapping binding sites in the transmembrane domain of the Smoothened receptor

Abstract: 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 pe… Show more

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Cited by 51 publications
(59 citation statements)
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“…Furthermore, the phenomenon of allosteric regulation in the SMO binding site was also inferred from studies on other SMO ligands Hoch et al, 2015).…”
Section: Discussionmentioning
confidence: 99%
“…Furthermore, the phenomenon of allosteric regulation in the SMO binding site was also inferred from studies on other SMO ligands Hoch et al, 2015).…”
Section: Discussionmentioning
confidence: 99%
“…Particularly, 99 (MRT‐83) was showed to display potent inhibition against both human Smo‐WT and Smo‐D473H mutant ( K i = 4.6 and 5.5 nM, respectively). Further elongation of the biaryl moiety of compound 99 led to the discovery of 100 with a phenylethylphenyl tail . Compound 100 (MRT‐92) showed higher Hh inhibitory activity than 99 in the SHh light II Gli‐luc assay (IC 50 = 2.8 nM) and the alkaline phosphatase assay stimulation by SAG (IC 50 = 5.6 nM).…”
Section: Hh Signaling Pathway Inhibitorsmentioning
confidence: 99%
“…36 Crystal structures of various SMO/ligand complexes have revealed a narrow hydrophobic cavity extending from the extracellular loops into the heptahelical bundle. 26,3739 These studies suggest that SMO ligands can be grouped into at least three general classes: compounds that primarily bind to the extracellular entrance of the cavity (e.g., cyclopamine; see Figure 3C), those that penetrate deeply into the transmembrane cavity (e.g., SANT-1), and others that engage both sites (e.g., MRT-92; 10 , Figure 4A). …”
Section: Targeted Anticancer Therapiesmentioning
confidence: 99%