Epigenetic small-molecule screen for inhibition and reversal of acinar ductal metaplasia in mouse pancreatic organoids.

Autor:	Atanasova KR; Department of Medicinal Chemistry, College of Pharmacy, University of Florida, Gainesville, FL, United States.; Center for Natural Products, Drug Discovery and Development, College of Pharmacy, University of Florida, Gainesville, FL, United States., Perkins CM; Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, FL, United States., Ratnayake R; Department of Medicinal Chemistry, College of Pharmacy, University of Florida, Gainesville, FL, United States.; Center for Natural Products, Drug Discovery and Development, College of Pharmacy, University of Florida, Gainesville, FL, United States., Jiang J; Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, FL, United States., Chen QY; Department of Medicinal Chemistry, College of Pharmacy, University of Florida, Gainesville, FL, United States.; Center for Natural Products, Drug Discovery and Development, College of Pharmacy, University of Florida, Gainesville, FL, United States., Schmittgen TD; Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, FL, United States., Luesch H; Department of Medicinal Chemistry, College of Pharmacy, University of Florida, Gainesville, FL, United States.; Center for Natural Products, Drug Discovery and Development, College of Pharmacy, University of Florida, Gainesville, FL, United States.
Jazyk:	angličtina
Zdroj:	Frontiers in pharmacology [Front Pharmacol] 2024 Mar 06; Vol. 15, pp. 1335246. Date of Electronic Publication: 2024 Mar 06 (Print Publication: 2024).
DOI:	10.3389/fphar.2024.1335246
Abstrakt:	Background: Acinar ductal metaplasia (ADM) is among the earliest initiating events in pancreatic ductal adenocarcinoma (PDAC) development. Methods: We developed a novel morphology-based screen using organoids from wildtype and p48 Cre/+ (Cre) mice to discover epigenetic modulators that inhibit or reverse pancreatic ADM more effectively than the broad-spectrum HDAC inhibitor trichostatin A (TSA). Results: Of the 144 compounds screened, nine hits and two additional natural product HDAC inhibitors were validated by dose-response analysis. The class I HDAC inhibitors apicidin and FK228, and the histone methyltransferase inhibitor chaetocin demonstrated pronounced ADM inhibition and reversal without inducing significant cytotoxicity at 1 µM. Thioester prodrug class I HDAC inhibitor largazole attenuated ADM while its disulfide homodimer was effective in both ADM inhibition and reversal. Prioritized compounds were validated for ADM reversal in p48 Cre/+ ; LSL- Kras G12D/+ (KC) mouse organoids using both morphological and molecular endpoints. Molecular index analysis of ADM reversal in KC mouse organoids demonstrated improved activity compared to TSA. Improved prodrug stability translated into a stronger phenotypic and molecular response. RNA-sequencing indicated that angiotensinogen was the top inhibited pathway during ADM reversal. Conclusion: Our findings demonstrate a unique epigenetic mechanism and suggest that the phenotypic screen developed here may be applied to discover potential treatments for PDAC. Competing Interests: HL is cofounder of Oceanyx Pharmaceuticals, Inc., which is negotiating licenses for patent applications related to largazole. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. (Copyright © 2024 Atanasova, Perkins, Ratnayake, Jiang, Chen, Schmittgen and Luesch.)
Databáze:	MEDLINE
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