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用于抑制和逆转小鼠胰腺类器官中腺泡导管化生的表观遗传小分子筛选

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

作者信息

Atanasova Kalina R, Perkins Corey M, Ratnayake Ranjala, Jiang Jinmai, Chen Qi-Yin, Schmittgen Thomas D, Luesch Hendrik

机构信息

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.

出版信息

Front Pharmacol. 2024 Mar 6;15:1335246. doi: 10.3389/fphar.2024.1335246. eCollection 2024.

DOI:10.3389/fphar.2024.1335246
PMID:38510657
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10953826/
Abstract

Acinar ductal metaplasia (ADM) is among the earliest initiating events in pancreatic ductal adenocarcinoma (PDAC) development. We developed a novel morphology-based screen using organoids from wildtype and (Cre) mice to discover epigenetic modulators that inhibit or reverse pancreatic ADM more effectively than the broad-spectrum HDAC inhibitor trichostatin A (TSA). 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 ; LSL- (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. Our findings demonstrate a unique epigenetic mechanism and suggest that the phenotypic screen developed here may be applied to discover potential treatments for PDAC.

摘要

腺泡导管化生（ADM）是胰腺导管腺癌（PDAC）发生过程中最早的起始事件之一。我们利用野生型和（Cre）小鼠的类器官开发了一种基于形态学的新型筛选方法，以发现比广谱组蛋白去乙酰化酶抑制剂曲古抑菌素A（TSA）更有效地抑制或逆转胰腺ADM的表观遗传调节剂。在筛选的144种化合物中，通过剂量反应分析验证了9种活性化合物和另外两种天然产物组蛋白去乙酰化酶抑制剂。I类组蛋白去乙酰化酶抑制剂阿皮西丁和FK228，以及组蛋白甲基转移酶抑制剂毛壳菌素在1 μM时表现出显著的ADM抑制和逆转作用，且未诱导明显的细胞毒性。硫酯前体药物I类组蛋白去乙酰化酶抑制剂拉戈唑减弱了ADM，而其二硫键同型二聚体在ADM抑制和逆转方面均有效。使用形态学和分子终点对筛选出的化合物在LSL-（KC）小鼠类器官中进行ADM逆转验证。对KC小鼠类器官中ADM逆转的分子指标分析表明，与TSA相比，其活性有所提高。前体药物稳定性的提高转化为更强的表型和分子反应。RNA测序表明，血管紧张素原是ADM逆转过程中受抑制最明显的信号通路。我们的研究结果揭示了一种独特的表观遗传机制，并表明本文开发的表型筛选方法可用于发现PDAC的潜在治疗方法。

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