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  3. Repurposing antiparasitic antimonials to noncovalently rescue temperature-sensitive p53 mutations

Repurposing antiparasitic antimonials to noncovalently rescue temperature-sensitive p53 mutations

  • Cell Rep. 2022 Apr 12;39(2):110622. doi: 10.1016/j.celrep.2022.110622.
Yigang Tang 1,  Huaxin Song 1,  Zhengyuan Wang 1,  Shujun Xiao 1,  Xinrong Xiang 2,  Huien Zhan 3,  Lili Wu 1,  Jiale Wu 1,  Yangfei Xing 1,  Yun Tan 1,  Ying Liang 1,  Ni Yan 1,  Yuntong Li 1,  Jiabing Li 1,  Jiaqi Wu 1,  Derun Zheng 1,  Yunchuan Jia 1,  Zhiming Chen 1,  Yunqi Li 1,  Qianqian Zhang 1,  Jianming Zhang 1,  Hui Zeng 3,  Wei Tao 4,  Feng Liu 5,  Yu Wu 6,  Min Lu 7
Affiliations

Affiliations

  • 1 Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
  • 2 Department of Hematology, Hematology Research Laboratory, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China.
  • 3 Department of Hematology, The First Affiliated Hospital of Jinan University, Guangzhou 510632, Guangdong, China.
  • 4 Department of Hematology, The People's Hospital of Jianyang City, Jianyang 641400, Sichuan, China.
  • 5 Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China. Electronic address: [email protected].
  • 6 Department of Hematology, Hematology Research Laboratory, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China. Electronic address: [email protected].
  • 7 Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China. Electronic address: [email protected].
PMID: 35417717 DOI: 10.1016/j.celrep.2022.110622
Abstract

The tumor suppressor p53 is inactivated by over hundreds of heterogenous mutations in Cancer. Here, we purposefully selected phenotypically reversible temperature-sensitive (TS) p53 mutations for pharmacological rescue with thermostability as the compound-screening readout. This rational screening identified antiparasitic drug potassium antimony tartrate (PAT) as an agent that can thermostabilize the representative TS mutant p53-V272M via noncovalent binding. PAT met the three basic criteria for a targeted drug: availability of a co-crystal structure, compatible structure-activity relationship, and intracellular target specificity, consequently exhibiting antitumor activity in a xenograft mouse model. At the antimony dose in clinical antiparasitic therapy, PAT effectively and specifically rescued p53-V272M in patient-derived primary leukemia cells in single-cell RNA sequencing. Further scanning of 815 frequent p53-missense mutations identified 65 potential PAT-treatable mutations, most of which were temperature sensitive. These results lay the groundwork for repurposing noncovalent antiparasitic antimonials for precisely treating cancers with the 65 p53 mutations.

Keywords

CP: Cancer; antimonials; drug repurposing; precision medicine; temperature-sensitive mutations; tumor suppressor p53.

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