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发现AK-1690:一种强大且高度选择性的STAT6 PROTAC降解剂

Atsunori Kaneshige^1,2, Yiqing Yang², Longchuan Bai²

¹Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor, Michigan 48109, United States.

Journal of medicinal chemistry

|September 23, 2024

概括

研究人员开发了AK-1690,是一种针对STAT6 (信号转换器和转录激活器6) 的新型PROTAC降解剂. 这种强大的化合物有效降解细胞和组织中的STAT6蛋白,为研究疾病中的STAT6提供了一个新的工具.

科学领域:

分子生物学分子生物学
药物发现药物发现药物发现
生物化学生物化学

背景情况:

信号转换器和转录激活器6 (STAT6) 是一种关键蛋白质,与人类癌症和其他疾病有关.
向STAT6提供了一个有前途的治疗策略,但需要强效和选择性抑制剂.

研究的目的:

为STAT6.6开发一种强效和选择性降解剂.
研究新型STAT6向化合物的疗效和机制.

主要方法:

开发一种具有改善结合亲和力和选择性的STAT6配体.
使用STAT6连接体和脑连接体,设计和合成一种化向化体 (PROTAC).
在体外和体内对STAT6降解的评估.
同结晶学以确定相互作用的结构基础.

主要成果:

鉴定AK-068,一种STAT6配体,具有纳米分子结合亲和力和对STAT5.5的高选择性.
发现AK-1690,第一个强效和选择性的PROTAC STAT6降解剂,在皮科莫拉到纳米分子度 (DC50低至1nM) 实现STAT6降解.
AK-1690对其他STAT家族成员的影响最小,高达10μM,并且在小鼠组织中有效地减少了STAT6.
确定了STAT6与AK-1690的第一个共同晶体结构,阐明了相互作用机制.

结论:

作为STAT6.6的有力和选择性的PROTAC降解剂,AK-1690代表了显著的进步.
这种化合物作为一种有价值的工具来探索STAT6在生物过程和疾病发病过程中的功能.
AK-1690作为进一步治疗STAT6依赖性疾病的首要化合物具有前景.

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