Institute of Pharmacology & Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, PR China; Center for Drug Safety Evaluation and Research of ZJU, Hangzhou, 310058, PR China; Innovation Institute for Artificial Intelligence in Medicine, Zhejiang University, Hangzhou, 310016, PR China.
School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023, PR China; National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, PR China.
Eur J Med Chem. 2022 Aug 5;238:114459. doi: 10.1016/j.ejmech.2022.114459. Epub 2022 May 19.
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 及其相关信号通路已被认为是很有前途的治疗靶点，越来越多的证据表明，抑制或降解细胞内 AKT 是治疗癌症的可行策略。受合理连接子设计的计算建模方法指导，并基于我们在该领域的先前工作，我们在此高效合成了一小组招募 cereblon 的 AKT PROTAC 分子，并鉴定出一种非常有效的 AKT 降解剂 B4。与现有的 AKT 降解剂相比，B4 具有独特的结构，其 AKT 靶向弹头来源于吡唑-呋喃共轭哌啶衍生物。它诱导 AKT 的所有三种同工型选择性降解，并对几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 对 AKT 下游信号的抑制作用优于其母体抑制剂。B4 与其活性类似物一起，扩大了 AKT 化学降解剂的武器库，可作为揭示 AKT 新功能的宝贵探针，以及治疗癌症的潜在候选药物。
