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Indolactam Dipeptides as Nanomolar Gli Inhibitors

Mendoza, Manuel and Tran, UyenPhuong and Zhang, Grace C. and Leister, Jeffrey and To, Kyle and Malepeai-Tofaeono, Theodore and Ondrus, Alison E. and Billingsley, Kelvin L. (2022) Indolactam Dipeptides as Nanomolar Gli Inhibitors. ACS Medicinal Chemistry Letters, 13 (7). pp. 1036-1042. ISSN 1948-5875. PMCID PMC9290001. doi:10.1021/acsmedchemlett.1c00562. https://resolver.caltech.edu/CaltechAUTHORS:20220606-736156000

[img] PDF (Experimental procedures and characterization of synthesized compounds; methods for cell-based assays, including Shh-LIGHT2, Sufu-KO-LIGHT, NIH-3T3, C3H10T1/2, and ASZ001; and ¹H NMR spectra for 2 and 8) - Supplemental Material
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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.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1021/acsmedchemlett.1c00562DOIArticle
ORCID:
AuthorORCID
Tran, UyenPhuong0000-0001-5712-3974
Zhang, Grace C.0000-0002-2044-9230
Ondrus, Alison E.0000-0002-6023-3290
Billingsley, Kelvin L.0000-0001-9071-5170
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.
Funders:
Funding AgencyGrant Number
NSFCHE-1726903
NIH Predoctoral FellowshipGM07616
California State University, FullertonUNSPECIFIED
University of Illinois, ChicagoUNSPECIFIED
Subject Keywords:Hedgehog signaling pathway, Gli, protein kinase C, indolactam, inhibitor, basal cell carcinoma
Issue or Number:7
PubMed Central ID:PMC9290001
DOI:10.1021/acsmedchemlett.1c00562
Record Number:CaltechAUTHORS:20220606-736156000
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20220606-736156000
Official Citation:Indolactam Dipeptides as Nanomolar Gli Inhibitors. Manuel Mendoza, UyenPhuong Tran, Grace C. Zhang, Jeffrey Leister, Kyle To, Theodore Malepeai-Tofaeono, Alison E. Ondrus, and Kelvin L. Billingsley. ACS Medicinal Chemistry Letters 2022 13 (7), 1036-1042; DOI: 10.1021/acsmedchemlett.1c00562
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:115032
Collection:CaltechAUTHORS
Deposited By: George Porter
Deposited On:07 Jun 2022 15:36
Last Modified:01 Aug 2022 21:48

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