2. Academic Validation
  3. Selective Covalent Targeting of Pyruvate Kinase M2 Using Arsenous Warheads

Selective Covalent Targeting of Pyruvate Kinase M2 Using Arsenous Warheads

  • J Med Chem. 2023 Feb 23;66(4):2608-2621. doi: 10.1021/acs.jmedchem.2c01563.
Jingyao Wang 1 2,  Shaoqing Zhou 1 2,  Yan Cheng 1,  Lin Cheng 3 4,  Ying Qin 1 2,  Zhenfeng Zhang 3 4,  Aiwei Bi 2 5,  Huaijiang Xiang 1 2,  Xinheng He 3,  Xiaoxu Tian 6,  Wenbin Liu 1,  Jian Zhang 3,  Chao Peng 6,  Zhengjiang Zhu 1,  Min Huang 5,  Ying Li 1,  Guanglei Zhuang 3 4,  Li Tan 1
Affiliations

Affiliations

  • 1 Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 201210, China.
  • 2 University of Chinese Academy of Sciences, Beijing 100049, China.
  • 3 State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200240, China.
  • 4 Shanghai Key Laboratory of Gynecologic Oncology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200240, China.
  • 5 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • 6 National Facility for Protein Science in Shanghai, Zhangjiang Lab, Shanghai Advanced Research Institute, Chinese Academy of Sciences, Shanghai 201210, China.
PMID: 36723914 DOI: 10.1021/acs.jmedchem.2c01563
Abstract

There is growing interest in covalent targeted inhibitors in drug discovery against previously "undruggable" sites and targets. These molecules typically feature an electrophilic warhead that reacts with nucleophilic groups of protein residues, most notably the thiol group of cysteines. One main challenge in the field is to develop versatile utilizable warheads. Here, we characterize the unique features of novel arsenous warheads for reaction with thiol species in a reversible manner and further demonstrate that organoarsenic probes can be chemically tuned toward specific molecular targets by developing selective and potent inhibitors of Pyruvate Kinase M2 (PKM2). We show that compound 24 is a covalent and allosteric inhibitor of PKM2 and its orally bioavailable prodrug 25 exerts efficacious inhibition of PKM2-dependent tumor growth in vitro and in vivo. Our results introduce 25 and its derivatives as useful pharmacological tools and provide a general road map for targeting the protein cysteinome using arsenous warheads.

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