APR-246 reactivates mutant p53 by targeting cysteines 124 and 277
作者： Qiang Zhang , Vladimir J.N. Bykov , Klas G. Wiman , Joanna Zawacka-Pankau
DOI: 10.1101/214049
关键词:
摘要: The TP53 tumor suppressor gene is frequently inactivated in human tumors by missense mutations the DNA binding domain. lead to protein unfolding, decreased thermostability and loss of transcription factor function. Pharmacological targeting mutant p53 restore its function a promising strategy for cancer therapy. reactivating compound APR-246 (PRIMA-1Met) has been successfully tested phase I/IIa clinical trial. converted reactive electrophile methylene quinuclidinone (MQ), which binds covalently core We identified cysteine 277 as prime target MQ p53. Cys277 also essential MQ-mediated thermostabilization wild-type, R175H R273H p53, while both Cys124 are required APR-246-mediated functional restoration living cells. These findings may open opportunities rational design novel p53-targeting compounds.
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