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Published July 14, 2022 | Supplemental Material + Accepted Version
Journal Article Open

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 the growth of Gli-dependent basal cell carcinoma cells. More broadly, our structure–activity studies provide inroads for the development of novel Gli antagonists and new avenues for combating Gli-driven cancers.

Additional Information

© 2022 American Chemical Society. Received: October 14, 2021; Accepted: May 31, 2022; Published: June 3, 2022. We thank Prof. James K. Chen (Stanford University) for Shh-LIGHT2 and Sufu-KO-LIGHT, Prof. Scott Atwood (UC Irvine) for ASZ001 mBCC cells, and Prof. Nilay Patel (CSU Fullerton) for use of a GloMax luminometer. Instrumentation support was provided by the National Science Foundation MRI (CHE1726903) for acquisition of a UPLC-MS. G.C.Z. was supported through a training grant provided by the National Institutes of Health (NIH GM07616). This research was supported by funds granted by the Office of Research and Sponsored Projects at California State University, Fullerton (K.L.B.) and research funds from the Department of Chemistry at the University of Illinois Chicago (A.E.O.). Author Contributions. M.M. and U.T. contributed equally to this work. M.M., J.L., K.T., and T.M.-T. synthesized and characterized compounds. U.T. and G.C.Z. performed biological assays. K.L.B. and A.E.O. guided the experimentation and prepared the manuscript. The authors declare no competing financial interest.

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Accepted Version - ml1c00562.pdf

Supplemental Material - ml1c00562_si_001.pdf

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Created:
August 22, 2023
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January 18, 2024