正在进行临床开发的分化选择性 CDK9 抑制剂 YK-2168 的发现和临床前概况。

IF 2.5 4区医学 Q3 CHEMISTRY, MEDICINAL

Bioorganic & Medicinal Chemistry Letters Pub Date : 2024-09-01 DOI:10.1016/j.bmcl.2024.129941

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引用次数: 0

摘要

新出现的临床证据表明，选择性 CDK9 抑制剂可为某些癌症的治疗带来临床益处。许多 CDK9 选择性抑制剂已进入临床开发阶段，并正在接受研究。由于这些药物在临床上经常出现不可预见的毒性，因此还没有出现明显的赢家。因此，我们仍然需要一种具有差异化特征的新型药物。在此，我们报告了新型氮杂吲哚系列选择性 CDK9 抑制剂的设计和合成。通过 SAR 研究，我们得到了临床前候选药物 YK-2168。与 AZD4573 和 BAY1251152 相比，YK2168 表现出更好的 CDK9 选择性；在临床前研究中，YK2168 还表现出差异化的静脉 PK 谱，并在小鼠胃癌 SNU16 CDX 模型中显示出显著的实体瘤疗效。YK-2168 目前正在中国进行临床开发（CTR20212900）。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

Discovery and preclinical profile of YK-2168, a differentiated selective CDK9 inhibitor in clinical development

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Discovery and preclinical profile of YK-2168, a differentiated selective CDK9 inhibitor in clinical development

Emerging clinical evidence indicates that selective CDK9 inhibition may provide clinical benefits in the management of certain cancers. Many CDK9 selective inhibitors have entered clinical developments, and are being investigated. No clear winner has emerged because of unforeseen toxicity often observed in clinic with these agents. Therefore, a novel agent with differentiated profiles is still desirable. Herein, we report our design, syntheses of a novel azaindole series of selective CDK9 inhibitors. SAR studies led to a preclinical candidate YK-2168. YK2168 exhibited improved CDK9 selectivity over AZD4573 and BAY1251152; also showed differentiated intravenous PK profile and remarkable solid tumor efficacy in a mouse gastric cancer SNU16 CDX model in preclinical studies. YK-2168 is currently in clinical development in China (CTR20212900).

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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.