[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;42(3):325-327.
[2] Song, H., S. Xiao, J. Wu, M. Lu#. Drugging p53: Barriers, Criteria, and Prospects. Cancer Discov, 2024, 14(11): 2055-2060.
Abstract: Pharmacologically targeting tumor suppressors necessitates an unprecedented strategy of restoring, rather than conventionally inhibiting, protein function, and p53, the most commonly mutated protein in cancer, has thus remained undruggable. In this study, we address long-standing misconceptions in the field and gaps in the scientific logic for a p53 function-restoration strategy, identify four barriers for drugging mutant p53, and accordingly propose effectiveness evaluation criteria, clinical-translating norms, and prospects for mutant p53 rescue compounds.
[3] 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