PRIMA-1 Reactivates Mutant p53 by Covalent Binding to the Core Domain
PRIMA-1 Reactivates Mutant p53 by Covalent Binding to the Core Domain
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DOI：
10.1016/j.ccr.2009.03.003
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发表时间：
2009-05-05
期刊：
影响因子：
50.3
通讯作者：
Bykov, Vladimir J. N.
中科院分区：
文献类型：
--
作者：
Lambert, Jeremy M. R.;Gorzov, Petr;Bykov, Vladimir J. N.
野生型p53表达的恢复触发细胞死亡并消除体内肿瘤。突变型p53再活化小分子如PRIMA-1的鉴定为开发更有效的抗癌药物开辟了可能性。虽然PRIMA-1的生物学效应已得到充分证实，但对其作用的分子机制知之甚少。我们在这里显示，PRIMA-1被转化为与突变型p53中的硫醇形成加合物的化合物。突变型p53本身的共价修饰足以诱导肿瘤细胞的凋亡。这些发现可能有助于设计更有效和更特异的突变型p53靶向抗癌药物。
Restoration of wild-type p53 expression triggers cell death and eliminates tumors in vivo. The identification of mutant p53-reactivating small molecules such as PRIMA-1 opens possibilities for the development of more efficient anticancer drugs. Although the biological effects of PRIMA-1 are well demonstrated, little is known about its molecular mechanism of action. We show here that PRIMA-1 is converted to compounds that form adducts with thiols in mutant p53. Covalent modification of mutant p53 per se is sufficient to induce apoptosis in tumor cells. These findings might facilitate the design of more potent and specific mutant p53-targeting anticancer drugs.