Novel-smoothened inhibitors for therapeutic targeting of naïve and drug-resistant hedgehog pathway-driven cancers

Acta Pharmacologica Sinica
Qing-Rou LiKer Yu

Abstract

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...Continue Reading

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Citations

Aug 12, 2018·International Journal of Molecular Sciences·Agnese PoZein Mersini Besharat
Sep 24, 2020·International Journal of Molecular Sciences·Kuo-Shyang JengChiung-Fang Chang
Jul 18, 2020·Frontiers in Oncology·Enrico FranceschiUNKNOWN EURACAN Domain 10
Mar 15, 2019·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Anna A KiselevaErica A Golemis
Dec 5, 2020·Trends in Genetics : TIG·Jesus Garcia-LopezPaul A Northcott
Mar 4, 2021·Cell & Bioscience·Junwan FanWei Chen
Mar 23, 2021·Mediators of Inflammation·Niti KumariBrian J North
Jun 12, 2021·Stem Cell Reviews and Reports·Mojgan BaratiSeyedeh-Nafiseh Hassani
Aug 28, 2021·International Journal of Molecular Sciences·Ana María ZárateCristian O Salas

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