Indolactam Dipeptides as Nanomolar Gli Inhibitors.

ABSTRACT: The Gli transcription factors within the Hedgehog (Hh) signaling pathway play essential roles in human development. However, the reactivation of Gli proteins in adult tissue is tumorigenic and drives the progression of several cancers, including the majority of basal cell carcinomas. Here we describe a novel set of indolactam dipeptides that target protein kinase C (PKC), exploiting the unique capacity of PKC isozymes to act as regulators of Gli. We devised an efficient synthetic route for the indolactam-based natural product (-)-pendolmycin and a series of analogues, and we evaluated these analogues in mechanistically distinct Gli reporter assays. The lead compound from these studies, N-hexylindolactam V, exhibits superior Gli suppression relative to clinical inhibitors and blocks

SUBMITTER: Mendoza M 

PROVIDER: S-EPMC9290001 | biostudies-literature | 2022 Jul

REPOSITORIES: biostudies-literature