[1] Xiao S*, Shi F*, Song H*, Cui J*, Zheng D, Zhang H, Tan K, Wu J, Chen X, Wu J, Tang Y, Dai Y, Lu M#: Characterization of the generic mutant p53-rescue compounds in a broad range of assays. Cancer Cell 2024, accepted.
[2] Song H*, Wu J*, Tang Y*, Dai Y*, Xiang X, Li Y, Wu L, Wu J, Liang Y, Xing Y, Yan N, Li Y, Wang Z, Xiao S, Li J, Zheng D, Chen X, Fang H, Ye C, Ma Y, Wu Y, Wu W, Li J, Zhang S, Lu M#. Science Translational Medicine 2023, 15:eabn9155.

Abstract: Tumor suppressor p53 is inactivated by thousands of heterogeneous mutations in cancer, but their individual druggability remains largely elusive. Here, we evaluated 800 common p53 mutants for their rescue potencies by the representative generic rescue compound arsenic trioxide (ATO) in terms of transactivation activity, cell growth inhibition, and mouse tumor-suppressive activities. The rescue potencies were mainly determined by the solvent accessibility of the mutated residue, a key factor determining whether a mutation is a structural one, and the temperature sensitivity, the ability to reassemble the wild-type DNA binding surface at a low temperature, of the mutant protein. A total of 390 p53 mutants were rescued to varying degrees and thus were termed as type 1, type 2a, and type 2b mutations, depending on the degree to which they were rescued. The 33 type 1 mutations were rescued to amounts comparable to the wild type. In PDX mouse trials, ATO preferentially inhibited growth of tumors harboring type 1 and type 2a mutants. In an ATO clinical trial, we report the first-in-human mutant p53 reactivation in a patient harboring the type 1 V272M mutant. In 47 cell lines derived from 10 cancer types, ATO preferentially and effectively rescued type 1 and type 2a mutants, supporting the broad applicability of ATO in rescuing mutant p53. Our study provides the scientific and clinical communities with a resource of the druggabilities of numerous p53 mutations (www.rescuep53.net)and proposes a conceptual p53-targeting strategy based on individual mutant alleles rather than mutation type.

https://pubmed.ncbi.nlm.nih.gov/37018419/
https://mp.weixin.qq.com/s/axD9EadmUYC5eYFGgtShHg; 
https://www.science.org/stoken/author-tokens/ST-1114/full
[3] 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