[4] Chen S*, Wu J*, Liang Y*, Tang Y*, Song H, Wu L, Xing Y, Yan N, Li Y, Wang Z, Xiao S, Lu X#, Chen S,Lu M#. Cancer Cell 2021;39(2):225-239.e8.

Abstract: TP53 is the most frequently mutated gene in cancer, yet these mutations remain therapeutically non-actionable. Major challenges in drugging p53 mutations include heterogeneous mechanisms of inactivation and the absence of broadly applicable allosteric sites. Here we report the identification of small molecules, including arsenic trioxide (ATO), an established agent in treating acute promyelocytic leukemia, as cysteine-reactive compounds that rescue structural p53 mutations. Crystal structures of arsenic-bound p53 mutants reveal a cryptic allosteric site involving three arsenic-coordinating cysteines within the DNA-binding domain, distal to the zinc-binding site. Arsenic binding stabilizes the DNA-binding loop-sheet-helix motif alongside the overall beta-sandwich fold, endowing p53 mutants with thermostability and transcriptional activity. In cellular and mouse xenograft models, ATO reactivates mutant p53 for tumor suppression. Investigation of the 25 most frequent p53 mutations informs patient stratification for clinical exploration. Our results provide a mechanistic basis for repurposing ATO to target p53 mutations for widely applicable yet personalized cancer therapies.
https://pubmed.ncbi.nlm.nih.gov/33357454/

https://mp.weixin.qq.com/s/HXE_AdbVSS0gbV4jVkfgJw

[5] Tang Y*, Song H*, Wang Z*, Xiao S*, Xiang X, Zhan H, Wu L, Wu J, Xing Y, Tan Y, Liang Y, Yan N, Li Y, Li J, Wu J, Zheng D, Jia Y, Chen Z, Li Y, Zhang Q, Zhang J, Zeng H, Tao W, Liu F#, Wu Y#, Lu M#. Cell Reports 2022;39(2):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.
https://pubmed.ncbi.nlm.nih.gov/35417717/

[6] Liang Y*, An Q*, Song H*, Tang Y*, Xiao S, Wu J, Yan N, Yu B, Cao X#, Lu M#: AcGlcAs: A Novel P53-Targeting Arsenical with Potent Cellular Uptake and Cancer Cell Selectivity. Journal of Medicinal Chemistry 2023, 66:16579-96.
https://pubmed.ncbi.nlm.nih.gov/38069817/