Enhanced cellular death in liver and breast cancer cells by dual BET/BRPF1 inhibitors.

IF 4.5 3区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Protein Science Pub Date : 2024-11-01 DOI:10.1002/pro.5191

Giulia Cazzanelli, Andrea Dalle Vedove, Nicolò Sbardellati, Luca Valer, Amedeo Caflisch, Graziano Lolli

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Abstract

The acetylpyrrole scaffold is an acetylated lysine mimic that has been previously explored to develop bromodomain inhibitors. When tested on the hepatoma cell line Huh7 and the breast cancer cell line MDA-MB-231, a few compounds in our acetylpyrrole-thiazole library induced peculiar morphological changes, progressively causing cell death at increasing concentrations. Their evaluation on a panel of human bromodomains revealed concurrent inhibition of BRPF1 and BET bromodomains. To dissect the observed cellular effects, the acetylpyrrole derivatives were compared to JQ1 and GSK6853, chemical probes for the bromodomains of BET and BRPF1, respectively. The appearance of neurite-like extrusions, accompanied by βIII-tubulin overexpression, is caused by BET inhibition, with limited effect on cellular viability. Conversely, interference with BRPF1 induces cellular death but not phenotypic alterations. Combined treatment with JQ1 and GSK6853 showed additivity in reducing cellular viability, comparably to the acetylpyrrole-thiazole-based BET/BRPF1 inhibitors. In addition, we determined the crystallographic structures of the BRD4 and BRPF1 bromodomains in complex with the acetylpyrrole-thiazole compounds. The binding modes in the two bromodomains show similar interactions for the acetylpyrrole and different orientations of the moiety that point to the rim of the acetyl-lysine pocket.

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BET/BRPF1 双重抑制剂可增强肝癌和乳腺癌细胞的细胞死亡。

乙酰吡咯支架是一种乙酰化赖氨酸模拟物，以前曾被用来开发溴结构域抑制剂。在对肝癌细胞系 Huh7 和乳腺癌细胞系 MDA-MB-231 进行测试时，我们的乙酰基吡咯-噻唑化合物库中的一些化合物诱发了奇特的形态变化，浓度增加时会逐渐导致细胞死亡。在对人类溴化基因组进行评估后发现，这些化合物同时抑制了 BRPF1 和 BET 溴化基因组。为了分析观察到的细胞效应，我们将乙酰吡咯衍生物与 JQ1 和 GSK6853 进行了比较。抑制 BET 会导致神经元样挤压的出现，并伴随着βⅢ-微管蛋白的过度表达，但对细胞活力的影响有限。相反，干扰 BRPF1 会诱导细胞死亡，但不会引起表型改变。JQ1和GSK6853的联合治疗在降低细胞活力方面显示出相加作用，与乙酰吡咯-噻唑类BET/BRPF1抑制剂相当。此外，我们还测定了 BRD4 和 BRPF1 溴基团与乙酰吡咯-噻唑化合物复合物的晶体结构。这两种溴结构域的结合模式显示，乙酰吡咯的相互作用相似，而指向乙酰基-赖氨酸口袋边缘的分子取向不同。

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来源期刊

Protein Science 生物-生化与分子生物学

CiteScore

12.40

自引率

1.20%

发文量

246

审稿时长

1 months

期刊介绍： Protein Science, the flagship journal of The Protein Society, is a publication that focuses on advancing fundamental knowledge in the field of protein molecules. The journal welcomes original reports and review articles that contribute to our understanding of protein function, structure, folding, design, and evolution. Additionally, Protein Science encourages papers that explore the applications of protein science in various areas such as therapeutics, protein-based biomaterials, bionanotechnology, synthetic biology, and bioelectronics. The journal accepts manuscript submissions in any suitable format for review, with the requirement of converting the manuscript to journal-style format only upon acceptance for publication. Protein Science is indexed and abstracted in numerous databases, including the Agricultural & Environmental Science Database (ProQuest), Biological Science Database (ProQuest), CAS: Chemical Abstracts Service (ACS), Embase (Elsevier), Health & Medical Collection (ProQuest), Health Research Premium Collection (ProQuest), Materials Science & Engineering Database (ProQuest), MEDLINE/PubMed (NLM), Natural Science Collection (ProQuest), and SciTech Premium Collection (ProQuest).