发现一种可口服的强效吡唑并吡啶酮衍生物，作为新型选择性溴结构域和外端结构域 (BET) - 第一溴结构域 (BD1) 抑制剂。

IF 2.5 4区医学 Q3 CHEMISTRY, MEDICINAL Bioorganic & Medicinal Chemistry Letters Pub Date : 2024-06-12 DOI:10.1016/j.bmcl.2024.129849

Shuichi Hagihara, Kouhei Ishizawa, Kana Soga, Takashi Honjo, Shigeki Takai, Yuko Kawano, Manami Kikuchi, Akiko Nishidate, Fumi Matsumoto, Mikako Murase, Naohiro Hashimoto, Chiduko Sasaki, Ikuko Miyaguchi, Okimasa Okada, Tomoya Akashi, Shinji Nakayama, Yuko Ogasawara, Junichi Endo

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引用次数: 0

摘要

临床研究表明，溴域和端外域（BET）蛋白，尤其是 BRD4 的抑制剂具有抗肿瘤活性和疗效。BET 蛋白有两个结构域，即 BD1 和 BD2，我们以前主要研究 BD1，并报道了口服生物可用的 BD1 选择性抑制剂。在本研究中，我们获得了一种 BD1 抑制剂--一种更有效、高选择性的吡唑并吡啶酮衍生物 13a，并证实了其体内疗效。

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Discovery of a potent orally available pyrazolopyridone derivative as a novel selective bromodomain and extra-terminal domain (BET)-first bromodomain (BD1) inhibitor

Clinical studies have shown that inhibitors of bromodomain and extra-terminal domain (BET) proteins, particularly BRD4, have antitumor activity and efficacy. The BET protein has two domains, BD1 and BD2, and we previously focused on BD1 and reported orally bioavailable BD1-selective inhibitors. In this study, we obtained a BD1 inhibitor, a more potent and highly selective pyrazolopyridone derivative 13a, and confirmed its in vivo efficacy.

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来源期刊

Bioorganic & Medicinal Chemistry Letters 医学-医药化学

CiteScore

5.70

自引率

3.70%

发文量

463

审稿时长

27 days

期刊介绍： Bioorganic & Medicinal Chemistry Letters presents preliminary experimental or theoretical research results of outstanding significance and timeliness on all aspects of science at the interface of chemistry and biology and on major advances in drug design and development. The journal publishes articles in the form of communications reporting experimental or theoretical results of special interest, and strives to provide maximum dissemination to a large, international audience.