2. Academic Validation
  3. Discovery of compounds that reactivate p53 mutants in vitro and in vivo

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

  • Cell Chem Biol. 2022 Sep 15;29(9):1381-1395.e13. doi: 10.1016/j.chembiol.2022.07.003.
Geetha Durairaj 1,  Özlem Demir 2,  Bryant Lim 3,  Roberta Baronio 4,  Delia Tifrea 5,  Linda V Hall 4,  Jacob C DeForest 3,  Linda Lauinger 4,  Maryam M Jebril Fallatah 4,  Clinton Yu 6,  Hosung Bae 4,  Da-Wei Lin 4,  Jin Kwang Kim 4,  Faezeh Salehi 7,  Cholsoon Jang 4,  Feng Qiao 4,  Richard H Lathrop 8,  Lan Huang 6,  Robert Edwards 5,  Scott Rychnovsky 3,  Rommie E Amaro 9,  Peter Kaiser 10
Affiliations

Affiliations

  • 1 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.
  • 2 Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA 92093, USA.
  • 3 Department of Chemistry, University of California, Irvine, Irvine, CA 92697, USA.
  • 4 Department of Biological Chemistry, University of California, Irvine, Irvine, CA 92697, USA.
  • 5 Department of Pathology and Laboratory Medicine, University of California, Irvine, Irvine, CA 92697, USA.
  • 6 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.
  • 7 Department of Computer Science, University of California, Irvine, Irvine, CA 92697, USA.
  • 8 Department of Computer Science, University of California, Irvine, Irvine, CA 92697, USA; Department of Biomedical Engineering, University of California, Irvine, Irvine, CA 92697, USA.
  • 9 Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA 92093, USA. Electronic address: ramaro@ucsd.edu.
  • 10 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.
PMID: 35948006 DOI: 10.1016/j.chembiol.2022.07.003
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.

Keywords

cryptic pocket; ensemble based virtual screening; molecular dynamics simulations; mutant p53; p53 reactivation; small molecule p53 corrector drugs.

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