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Mutant p53 reactivation by small molecules makes its way to the clinic
Author(s) -
Bykov Vladimir J.N.,
Wiman Klas G.
Publication year - 2014
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1016/j.febslet.2014.04.017
Subject(s) - mutant , biology , missense mutation , cancer research , suppressor , mutation , gene , programmed cell death , tumor suppressor gene , mutant protein , cell cycle checkpoint , phenotype , cancer , cell cycle , genetics , apoptosis , carcinogenesis
The TP53 tumor suppressor gene is mutated in many human tumors, including common types of cancer such as colon and ovarian cancer. This illustrates the key role of p53 as trigger of cell cycle arrest or cell death upon oncogenic stress. Most TP53 mutations are missense mutations that result in single amino acid substitutions in p53 and expression of high levels of dysfunctional p53 protein. Restoration of wild type p53 function in such tumor cells will induce robust cell death and allow efficient eradication of the tumor. Therapeutic targeting of mutant p53 in tumors is a rapidly developing field at the forefront of translational cancer research. Various approaches have led to the identification of small molecules that can rescue mutant p53. These include compounds that target specific p53 mutations, including PK083 and PK5174 (Y220C mutant p53) and NSC319726 (R175H mutant p53), as well as PRIMA‐1 and its analog APR‐246 that affect a wider range of mutant p53 proteins. APR‐246 has been tested in a Phase I/II clinical trial with promising results.