2. Academic Validation
  3. Identification of a druggable protein-protein interaction site between mutant p53 and its stabilizing chaperone DNAJA1

Identification of a druggable protein-protein interaction site between mutant p53 and its stabilizing chaperone DNAJA1

  • J Biol Chem. 2021 Jan-Jun;296:100098. doi: 10.1074/jbc.RA120.014749.
Xin Tong 1,  Dandan Xu 2,  Rama K Mishra 3,  Ryan D Jones 2,  Leyu Sun 2,  Gary E Schiltz 4,  Jie Liao 2,  Guang-Yu Yang 5
Affiliations

Affiliations

  • 1 Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA; Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
  • 2 Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
  • 3 Center for Molecular Innovation and Drug Discovery (CMIDD), Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA; Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA; Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
  • 4 Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA; Center for Molecular Innovation and Drug Discovery (CMIDD), Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA; Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
  • 5 Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA; Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA. Electronic address: g-yang@northwestern.edu.
PMID: 33208462 DOI: 10.1074/jbc.RA120.014749
Abstract

The TP53 gene is the most frequently mutated gene in human cancers, and the majority of TP53 mutations are missense mutations. As a result, these mutant p53 (mutp53) either directly lose wildtype p53 (wtp53) tumor suppressor function or exhibit a dominant negative effect over wtp53. In addition, some mutp53 have acquired new oncogenic function (gain of function). Therefore, targeting mutp53 for its degradation may serve as a promising strategy for Cancer prevention and therapy. Based on our previous finding that farnesylated DNAJA1 is a crucial chaperone in maintaining mutp53 stabilization, and by using an in silico approach, we built 3D homology models of human DNAJA1 and mutp53R175H proteins, identified the interacting pocket in the DNAJA1-mutp53R175H complex, and found one critical druggable small molecule binding site in the DNAJA1 glycine/phenylalanine-rich region. We confirmed that the interacting pocket in the DNAJA1-mutp53R175H complex was crucial for stabilizing mutp53R175H using a site-directed mutagenesis approach. We further screened a drug-like library to identify a promising small molecule hit (GY1-22) against the interacting pocket in the DNAJA1-mutp53R175H complex. The GY1-22 compound displayed an effective activity against the DNAJA1-mutp53R175H complex. Treatment with GY1-22 significantly reduced mutp53 protein levels, enhanced Waf1p21 expression, suppressed cyclin D1 expression, and inhibited mutp53-driven pancreatic Cancer growth both in vitro and in vivo. Together, our results indicate that the interacting pocket in the DNAJA1-mutp53R175H complex is critical for mutp53's stability and oncogenic function, and DNAJA1 is a robust therapeutic target for developing the efficient small molecule inhibitors against oncogenic mutp53.

Keywords

DNAJA1; homology model; in silico; interacting pocket; mutant p53; pancreatic cancer; protein–protein docking.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-149911
    DNAJA1-mutP53 R175H抑制剂
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