Journal article
Discovery of compounds that reactivate p53 mutants in vitro and in vivo
Cell chemical biology, Vol.29(9), pp.1381-1395.e13
09/15/2022
DOI: 10.1016/j.chembiol.2022.07.003
PMID: 35948006
Abstract
The tumor suppressor p53 is the most frequently mutated protein in human cancer. The majority of these mutations are missense mutations in the DNA binding domain of p53. Restoring p53 tumor suppressor function could have a major impact on the therapy for a wide range of cancers. Here we report a virtual screening approach that identified several small molecules with p53 reactivation activities. The UCI-LC0023 compound series was studied in detail and was shown to bind p53, induce a conformational change in mutant p53, restore the ability of p53 hotspot mutants to associate with chromatin, reestablish sequence-specific DNA binding of a p53 mutant in a reconstituted in vitro system, induce p53-dependent transcription programs, and prevent progression of tumors carrying mutant p53, but not p53null or p53WT alleles. Our study demonstrates feasibility of a computation-guided approach to identify small molecule corrector drugs for p53 hotspot mutations.
[Display omitted]
•Small molecules targeting a cryptic L1/S3 pocket of p53 are identified•Experimental validation led to the identification of mutant p53 reactivators•Compounds restore DNA binding of p53MUTin vitro and in vivo•Compounds directly bind to p53MUT and exert anti-tumor effect in tumor models
A large fraction of human tumors inactivate the major tumor suppressor p53 by mutations. Corrector drugs reactivating mutant p53 are of high clinical value for cancer therapy. Durairaj et al. identify small drug-like compounds that restore wild-type activity to mutant forms of p53 and exhibit anti-tumor effects.
Details
- Title: Subtitle
- Discovery of compounds that reactivate p53 mutants in vitro and in vivo
- Creators
- Geetha Durairaj - University of California, IrvineÖzlem Demir - University of California San DiegoBryant Lim - University of California, IrvineRoberta Baronio - University of California, IrvineDelia Tifrea - University of California, IrvineLinda V. Hall - University of California, IrvineJacob C. DeForest - University of California, IrvineLinda Lauinger - University of California, IrvineMaryam M. Jebril Fallatah - University of California, IrvineClinton Yu - University of California, IrvineHosung Bae - University of California, IrvineDa-Wei Lin - University of California, IrvineJin Kwang Kim - University of California, IrvineFaezeh Salehi - University of California, IrvineCholsoon Jang - University of California, IrvineFeng Qiao - University of California, IrvineRichard H. Lathrop - University of California, IrvineLan Huang - University of California, IrvineRobert Edwards - University of California, IrvineScott Rychnovsky - University of California, IrvineRommie E. Amaro - University of California San DiegoPeter Kaiser - University of California, Irvine
- Resource Type
- Journal article
- Publication Details
- Cell chemical biology, Vol.29(9), pp.1381-1395.e13
- DOI
- 10.1016/j.chembiol.2022.07.003
- PMID
- 35948006
- ISSN
- 2451-9456
- eISSN
- 2451-9456
- Publisher
- Elsevier Ltd
- Language
- English
- Date published
- 09/15/2022
- Academic Unit
- Internal Medicine
- Record Identifier
- 9985217035402771
Metrics
1 Record Views