Overcoming the resistance mechanisms of Smoothened inhibitors.

Overcoming the resistance mechanisms of Smoothened inhibitors.
Drug Discov Today. 2018 Jan 08;:
Authors: Dong X, Wang C, Chen Z, Zhao W
Abstract
Smoothened (Smo), the main transducer of the Hedgehog (Hh) signaling pathway, is a promising target for anticancer therapy. Although vismodegib and sonidegib have demonstrated effectiveness for the treatment of basal cell carcinoma (BCC), their clinical use has been associated with mutation-related drug resistance. In this review, we outline the resistance mechanisms of Smo inhibitors and point the way for future endeavors. We focus in particular on the development of second-generation Smo inhibitors based on co-crystal structures, inhibition of downstream components, and the regulation of other interacting pathways or mediators that could compensate for the inhibitory activity of upstream inhibitors.
PMID: 29326074 [PubMed - as supplied by publisher]

Source: Drug Discovery Today - January 8, 2018 Category: Drugs & Pharmacology Authors: Dong X, Wang C, Chen Z, Zhao W Tags: Drug Discov Today Source Type: research