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Discovery of an AKT Degrader with Prolonged Inhibition of Downstream Signaling.
Cell Chemical Biology ( IF 6.6 ) Pub Date : 2019-12-16 , DOI: 10.1016/j.chembiol.2019.11.014 Inchul You 1 , Emily C Erickson 2 , Katherine A Donovan 1 , Nicholas A Eleuteri 3 , Eric S Fischer 1 , Nathanael S Gray 1 , Alex Toker 2
Cell Chemical Biology ( IF 6.6 ) Pub Date : 2019-12-16 , DOI: 10.1016/j.chembiol.2019.11.014 Inchul You 1 , Emily C Erickson 2 , Katherine A Donovan 1 , Nicholas A Eleuteri 3 , Eric S Fischer 1 , Nathanael S Gray 1 , Alex Toker 2
Affiliation
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The PI3K/AKT signaling cascade is one of the most commonly dysregulated pathways in cancer, with over half of tumors exhibiting aberrant AKT activation. Although potent small-molecule AKT inhibitors have entered clinical trials, robust and durable therapeutic responses have not been observed. As an alternative strategy to target AKT, we report the development of INY-03-041, a pan-AKT degrader consisting of the ATP-competitive AKT inhibitor GDC-0068 conjugated to lenalidomide, a recruiter of the E3 ubiquitin ligase substrate adaptor Cereblon (CRBN). INY-03-041 induced potent degradation of all three AKT isoforms and displayed enhanced anti-proliferative effects relative to GDC-0068. Notably, INY-03-041 promoted sustained AKT degradation and inhibition of downstream signaling effects for up to 96 h, even after compound washout. Our findings suggest that AKT degradation may confer prolonged pharmacological effects compared with inhibition, and highlight the potential advantages of AKT-targeted degradation.
中文翻译：
发现AKT降解剂，具有延长抑制下游信号的能力。
PI3K / AKT信号级联是癌症中最常见的失调途径之一，一半以上的肿瘤表现出异常的AKT激活。尽管有效的小分子AKT抑制剂已进入临床试验，但尚未观察到强大而持久的治疗反应。作为靶向AKT的替代策略，我们报告了INY-03-041的开发，这是一种泛AKT降解物，由与alialidomide结合的ATP竞争性AKT抑制剂GDC-0068结合，来那度胺是E3泛素连接酶底物适配器Cereblon的募集者（ CRBN）。INY-03-041诱导了所有三种AKT亚型的有效降解，并且相对于GDC-0068表现出增强的抗增殖作用。值得注意的是，即使经过化合物冲洗，INY-03-041仍可促进AKT持续降解并抑制下游信号传导作用长达96小时。
更新日期：2019-12-17
中文翻译：
发现AKT降解剂，具有延长抑制下游信号的能力。
PI3K / AKT信号级联是癌症中最常见的失调途径之一，一半以上的肿瘤表现出异常的AKT激活。尽管有效的小分子AKT抑制剂已进入临床试验，但尚未观察到强大而持久的治疗反应。作为靶向AKT的替代策略，我们报告了INY-03-041的开发，这是一种泛AKT降解物，由与alialidomide结合的ATP竞争性AKT抑制剂GDC-0068结合，来那度胺是E3泛素连接酶底物适配器Cereblon的募集者（ CRBN）。INY-03-041诱导了所有三种AKT亚型的有效降解，并且相对于GDC-0068表现出增强的抗增殖作用。值得注意的是，即使经过化合物冲洗，INY-03-041仍可促进AKT持续降解并抑制下游信号传导作用长达96小时。
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