Abstract：
:Reactivation of mutant p53 has emerged as a promising approach for cancer therapy. Recent studies have identified several mutant p53-reactivating compounds that target thiol groups in mutant p53. Here we have investigated the relationship between thiol reactivity, p53 thermostabilization, mutant p53 refolding, mutant p53-dependent growth suppression, and induction of cell death. Analysis of the National Cancer Institute database revealed that Michael acceptors show the highest selectivity for mutant p53-expressing cells among analyzed thiol-reactive compounds. Further experimental testing demonstrated that Michael acceptors, aldehydes, imines, and primary alcohols can promote thermodynamic stabilization of mutant p53. Moreover, mild thiol reactivity, often coupled with combined chemical functional groups, such as in imines, aldehydes, and primary alcohols, can stimulate mutant p53 refolding. However, strong electrophile activity was associated with cellular toxicity. Our findings may open possibilities for rational design of novel potent and selective mutant p53-reactivating compounds.
journal_name
Cell Chem Bioljournal_title
Cell chemical biologyauthors
Zhang Q,Bergman J,Wiman KG,Bykov VJNdoi
10.1016/j.chembiol.2018.06.013subject
Has Abstractpub_date
2018-10-18 00:00:00pages
1219-1230.e3issue
10eissn
2451-9456issn
2451-9448pii
S2451-9456(18)30227-7journal_volume
25pub_type
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