Discovery of compounds that reactivate p53 mutants in vitro and in vivo.

Autor:	Durairaj G; Department of Biological Chemistry, University of California, Irvine, Irvine, CA 92697, USA; Chao Family Comprehensive Cancer Center, University of California, Irvine, Irvine, CA 92697, USA., Demir Ö; Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA 92093, USA., Lim B; Department of Chemistry, University of California, Irvine, Irvine, CA 92697, USA., Baronio R; Department of Biological Chemistry, University of California, Irvine, Irvine, CA 92697, USA., Tifrea D; Department of Pathology and Laboratory Medicine, University of California, Irvine, Irvine, CA 92697, USA., Hall LV; Department of Biological Chemistry, University of California, Irvine, Irvine, CA 92697, USA., DeForest JC; Department of Chemistry, University of California, Irvine, Irvine, CA 92697, USA., Lauinger L; Department of Biological Chemistry, University of California, Irvine, Irvine, CA 92697, USA., Jebril Fallatah MM; Department of Biological Chemistry, University of California, Irvine, Irvine, CA 92697, USA., Yu C; Department of Physiology and Biophysics, University of California, Irvine, Irvine, CA 92697, USA; Department of Developmental and Cell Biology, University of California, Irvine, Irvine, CA 92697, USA., Bae H; Department of Biological Chemistry, University of California, Irvine, Irvine, CA 92697, USA., Lin DW; Department of Biological Chemistry, University of California, Irvine, Irvine, CA 92697, USA., Kim JK; Department of Biological Chemistry, University of California, Irvine, Irvine, CA 92697, USA., Salehi F; Department of Computer Science, University of California, Irvine, Irvine, CA 92697, USA., Jang C; Department of Biological Chemistry, University of California, Irvine, Irvine, CA 92697, USA., Qiao F; Department of Biological Chemistry, University of California, Irvine, Irvine, CA 92697, USA., Lathrop RH; Department of Computer Science, University of California, Irvine, Irvine, CA 92697, USA; Department of Biomedical Engineering, University of California, Irvine, Irvine, CA 92697, USA., Huang L; Department of Physiology and Biophysics, University of California, Irvine, Irvine, CA 92697, USA; Department of Developmental and Cell Biology, University of California, Irvine, Irvine, CA 92697, USA., Edwards R; Department of Pathology and Laboratory Medicine, University of California, Irvine, Irvine, CA 92697, USA., Rychnovsky S; Department of Chemistry, University of California, Irvine, Irvine, CA 92697, USA., Amaro RE; Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA 92093, USA. Electronic address: ramaro@ucsd.edu., Kaiser P; Department of Biological Chemistry, University of California, Irvine, Irvine, CA 92697, USA; Chao Family Comprehensive Cancer Center, University of California, Irvine, Irvine, CA 92697, USA. Electronic address: pkaiser@uci.edu.
Jazyk:	angličtina
Zdroj:	Cell chemical biology [Cell Chem Biol] 2022 Sep 15; Vol. 29 (9), pp. 1381-1395.e13. Date of Electronic Publication: 2022 Aug 10.
DOI:	10.1016/j.chembiol.2022.07.003
Abstrakt:	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 p53 null or p53 WT alleles. Our study demonstrates feasibility of a computation-guided approach to identify small molecule corrector drugs for p53 hotspot mutations. Competing Interests: Declaration of interests Several authors of this manuscript are listed as inventors on the patent listed below. The patent describes compounds reported in this manuscript. Amaro, R. E., Baronio, R., Demir, O., Kaiser, P., Lathrop, R. H., Salehi-Amiri, S.-F., Wassman, C. Small molecules to enhance p53 activity. US patent US20160193214 A1. Approved March 2017. (Copyright © 2022 Elsevier Ltd. All rights reserved.)
Databáze:	MEDLINE
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