[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

[4] 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/

[5] 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/
[6] Wang Z*, Zhao Y*, Wang Q*, Xing Y*, Feng L, Kong J, Peng C, Zhang L#, Yang H#, Lu M#. Signal Transduction and Targeted Therapy 2021;6(1):214. 
https://pubmed.ncbi.nlm.nih.gov/34075025/ 

[7] Yan N*, Li Y*, Xing Y, Wu J, Li J, Liang Y, Tang Y, Wang Z, Song H, Wang H, Xiao S, Lu M#. EMBO Rep 2022;23(6):e54147.

Abstract: Developmental arsenic exposure has been associated with cognitive deficits in epidemiological studies, but the underlying mechanisms remain poorly understood. Here, we establish a mouse model of developmental arsenic exposure exhibiting deficits of recognition and spatial memory in the offspring. These deficits are associated with genome-wide DNA hypomethylation and abnormal expression of cognition-related genes in the hippocampus. Arsenic atoms directly bind to the cysteine-rich ADD domain of DNA methyltransferase 3A (DNMT3A), triggering ubiquitin- and proteasome-mediated degradation of DNMT3A in different cellular contexts. DNMT3A degradation leads to genome-wide DNA hypomethylation in mouse embryonic fibroblasts but not in non-embryonic cell lines. Treatment with metformin, a first-line antidiabetic agent reported to increase DNA methylation, ameliorates the behavioral deficits and normalizes the aberrant expression of cognition-related genes and DNA methylation in the hippocampus of arsenic-exposed offspring. Our study establishes a DNA hypomethylation effect of developmental arsenic exposure and proposes a potential treatment against cognitive deficits in the offspring of pregnant women in arsenic-contaminated areas.
https://pubmed.ncbi.nlm.nih.gov/35373418/

[8] Lu M, Zak J, Chen S, Sanchez-Pulido L, Severson DT, Endicott J, Ponting CP, Schofield CJ, Lu X#: A code for RanGDP binding in ankyrin repeats defines a nuclear import pathway. Cell 2014, 157:1130-45.
https://pubmed.ncbi.nlm.nih.gov/24855949/
[9] Lu M, Breyssens H, Salter V, Zhong S, Hu Y, Baer C, Ratnayaka I, Sullivan A, Brown NR, Endicott J, Knapp S, Kessler BM, Middleton MR, Siebold C, Jones EY, Sviderskaya EV, Cebon J, John T, Caballero OL, Goding CR, Lu X#: Restoring p53 function in human melanoma cells by inhibiting MDM2 and cyclin B1/CDK1-phosphorylated nuclear iASPP. Cancer Cell 2013, 23:618-33.
https://pubmed.ncbi.nlm.nih.gov/23623661/

[10] Lu M, Muers MR, Lu X#: Introducing STRaNDs: shuttling transcriptional regulators that are non-DNA binding. Nature Reviews Molecular Cell Biology 2016, 17:523-32.
https://pubmed.ncbi.nlm.nih.gov/27220640/