Novel-smoothened inhibitors for therapeutic targeting of na(i)ve and drug-resistant hedgehog pathway-driven cancers

• 来源期刊: 中国药理学报（英文版）
• 关键词: hedgehog smoothened inhibitor paracrine acquired drug resistance
• 年，卷（期）: 2019,（2）
• 页码范围: 257-267
• 页数: 11页
• 语种: 英文

摘要

The G protein-coupled receptor (GPCR) smoothened (SMO) is a key signaling component of the sonic hedgehog (Hh) pathway and a clinically validated target for cancer treatment.The FDA-approved SMO inhibitors GDC-0449/Vismodegib and LDE225/Sonidegib demonstrated clinical antitumor efficacy.Nevertheless,relatively high percentage of treated patients would eventually develop acquired cross resistance to both drugs.Here,based on published structure and activity of GDC-0449 inhibitor class,we replaced its amide core with benzimidazole which retained bulk of the SMO-targeting activity as measured in our Hh/SMO/Gli1-reporter system.Synthesis and screening of multiple series of benzimidazole derivatives identified HH-1,HH-13,and HH-20 with potent target suppression (IC50:＜0.1 μmol/L) in the reporter assays.In NIH3T3 cells stimulated with a secreted Hh (SHH),these inhibitors dose dependently reduced mRNA and protein expression of the endogenous pathway components PTCH-1,Gli1,and cyclin D1 resulting in growth inhibition via G0/G1 arrest.Mechanistically,the SMO-targeted growth inhibition involved downregulation of mTOR signaling inputs and readouts consistent with diminished mTORC1/mTORC2 functions and apoptosis.In mice,as with GDC-0449,orally administered HH inhibitors blocked paracrine activation of stromal Hh pathway in Calu-6 tumor microenvironment and attenuated growth of PTCH+/-/P53-/-medulloblastoma allograft tumors.Furthermore,HH-13 and HH-20 potently targeted the drug-resistant smoothened SMO-D473H (IC50:＜0.2 μmol/L) compared to the poor inhibition by GDC-0449 (IC50:＞60 μmol/L).These results identify HH-13 and HH-20 as potent inhibitors capable of targeting na(i)ve and drug-resistant Hh/SMO-driven cancers.The current leads may be optimized to improve pharmaceutical property for potential development of new therapy for treatment of Hh pathway-driven cancers.