AKT and associated signaling pathways have been recognized as promising therapeutic targets for decades, and growing evidence indicates that inhibition or degradation of cellular AKT are viable strategies to treat cancer. Guided by an in silico modeling approach for rational linker design and based on our previous work in this field, we herein efficiently synthesized a small group of cereblon-recruiting AKT PROTAC molecules and identified a highly potent AKT degrader B4. Compared to the existing AKT degraders, B4 has a structurally unique AKT targeting warhead derived from the pyrazole-furan conjugated piperidine derivatives. It induces selective degradation of all three isoforms of AKT and exhibits efficacious anti-proliferation against several human hematological cancers. Notably, B4 demonstrates potent inhibition of AKT downstream signaling superior to its parental inhibitor. Together with its active analogs, B4 expands the arsenal of AKT chemical degraders as a valuable probe to uncover AKTs new functions and as a potential drug candidate to treat cancer.

几十年来，AKT 和相关信号通路一直被认为是有前途的治疗靶点，并且越来越多的证据表明抑制或降解细胞 AKT 是治疗癌症的可行策略。在用于合理接头设计的计算机建模方法的指导下，并基于我们之前在该领域的工作，我们在此有效地合成了一小组大脑募集 AKT PROTAC 分子，并鉴定了一种高效的 AKT 降解剂B4。与现有的 AKT 降解剂相比，B4具有结构独特的 AKT 靶向弹头，源自吡唑-呋喃共轭哌啶衍生物。它诱导 AKT 的所有三种同种型的选择性降解，并对多种人类血液癌症表现出有效的抗增殖作用。值得注意的是，B4表现出优于其亲代抑制剂的 AKT 下游信号传导的有效抑制作用。B4与其活性类似物一起扩展了 AKT 化学降解剂的库，作为发现 AKT 新功能的有价值的探针，并作为治疗癌症的潜在候选药物。