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  3. Structure-based rational design enables efficient discovery of a new selective and potent AKT PROTAC degrader

Structure-based rational design enables efficient discovery of a new selective and potent AKT PROTAC degrader

  • Eur J Med Chem. 2022 Aug 5:238:114459. doi: 10.1016/j.ejmech.2022.114459.
Cheng-Liang Zhu 1,  Xiaomin Luo 2,  Tian Tian 3,  Zijian Rao 4,  Hanlin Wang 5,  Zhesheng Zhou 4,  Tian Mi 6,  Danni Chen 4,  Yongjin Xu 7,  Yizhe Wu 3,  Jinxin Che 3,  Yubo Zhou 8,  Jia Li 9,  Xiaowu Dong 10
Affiliations

Affiliations

  • 1 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.
  • 2 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.
  • 3 Hangzhou Institute of Innovative Medicine, Institute of Drug Discovery and Design, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, PR China.
  • 4 Institute of Pharmacology & Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, PR China.
  • 5 National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, PR China; School of Pharmacy, Fudan University, Shanghai, 200032, PR China.
  • 6 National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, PR China.
  • 7 Department of Lymphoma, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Basic Medicine and Cancer, Chinese Academy of Sciences, Hangzhou, 310005, PR China.
  • 8 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; Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan Tsuihang New District, Guangdong, 528400, PR China. Electronic address: ybzhou@simm.ac.cn.
  • 9 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; Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan Tsuihang New District, Guangdong, 528400, PR China. Electronic address: jli@simm.ac.cn.
  • 10 Hangzhou Institute of Innovative Medicine, Institute of Drug Discovery and Design, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, PR China; Innovation Institute for Artificial Intelligence in Medicine, Zhejiang University, Hangzhou, 310016, PR China; Cancer Center, Zhejiang University, Hangzhou, 310058, PR China. Electronic address: dongxw@zju.edu.cn.
PMID: 35635954 DOI: 10.1016/j.ejmech.2022.114459
Abstract

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.

Keywords

AKT; Chemical degrader; PROTAC; Protein kinase B; Rational design.

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