Small Molecule Antagonists in Distinct Binding Modes Inhibit Drug-Resistant Mutant of Smoothened

Abstract

Several small molecule antagonists for Smoothened (Smo) have been developed, and achieved promising preclinical efficacy in cancers that are dependent on Hedgehog (Hh) signaling. However, in a recent clinical study, a drug-resistant D473H SMO mutant was identified that is thought to be responsible for cancer relapse in a patient with medulloblastoma. Here, we report two Smo antagonists that bind to distinct sites, as compared to known antagonists and agonists, and inhibit both wild-type and mutant Smo. These findings provide an insight of the ligand-binding sites of Smo and a basis for the development of potential therapeutics for tumors with drug-resistant Smo mutations.

B4GALT1 gene knockdown inhibits the hedgehog pathway and reverses multidrug resistance in the human leukemia K562/adriamycin‐resistant cell line

“…It is considered to be an important target for overcoming drug resistance of cancer (41). The antagonists for Smo or GLI-1 were useful for inhibiting the Hh pathway and enhancing cytotoxicity of anticancer agents in tumors (42,43). Our study indicates that B4GALT1 inhibitor, which could overcome the limitation of targeting only one molecule in Hh signaling, might be a potential therapeutic option for the drug resistance of leukemia.…”

Biochemical characterization of smoothened receptor antagonists by binding kinetics against drug-resistant mutant

“…Various SMO antagonists have been shown to be active against SMO-D473H (Dijkgraaf et al, 2011;Ishii et al, 2014;Tao et al, 2011). For example, ALLO-1 and ALLO-2 inhibit SMO-WT and SMO-D473H with similar potencies.…”

GPCRs and cancer

“…However, the response of this patient to GDC-0449 treatment was only transient due to a mutation of Smo [71] . Recently, a number of Hh pathway antagonists targeting Smo mutants [72] as well as inhibitors able to block both wild-type and Smo mutants have been identified [73] . In addition to Smo antagonists, other inhibitors were used to block Hh signaling like the small molecule inhibitor of GLI1 and GLI2 transcription factors, GANT61, which induced colon carcinoma cell death in a higher extent respect to the conventional Smo inhibitor cyclopamin [74] .…”