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Accumulation of oncogenic mutant p53 (mutp53) greatly contributes to cancer progression. Heat shock protein 40 (HSP40), also known as J-domain protein (JDP), has been implicated in stabilization of misfolded mutp53. Recently, we demonstrate that knockdown of DNAJA1 results in degradation of mainly misfolded mutp53 and inhibition of tumor growth. Since no HSP40/JDP inhibitors are currently available in clinics, these findings have prompted us to identify potential HSP40/JDP inhibitors to induce mutp53 degradation.
To identify compounds that potentially bind to DNAJA1, we performed an in-silico docking study for the J-domain of DNAJA1. Identified compounds and their analogs were validated for their abilities to deplete misfolded p53 and/or DNAJA1 in multiple cancer cell lines.
The top 33 compounds were tested for their abilities to reduce the levels of misfolded mutp53 and DNAJA1, allowing us to identify the best candidate, namely #7-3. Eighteen commercially available analogs of #7-3 were further examined. Of these, a compound, namely B#2, had the strongest activity to deplete both DNAJA1 and misfolded mutp53. B#2 reduced misfolded mutp53 in a concentration-dependent and a time-dependent manner without affecting mRNA levels of mutp53. Importantly, B#2 showed minimal effects on the levels of wild-type p53 and DNA contact mutp53.
Our study, for the first time, has identified a small compound that may inhibit DNAJA1, leading to depletion of misfolded mutp53. This compound and its analogs could be used to inhibit tumor progression as potential novel anti-cancer agents.
Nishikawa, Shigeto; Kaida, Atsushi; Ranjan, Atul; Parrales, Alejandro; Alalem, Mohamed A.A.; Johnson, David; and Iwakuma, Tomoo, "Novel HSP40/J-Domain Protein Inhibitors To Deplete Misfolded Mutant P53" (2021). Research at Children's Mercy Month 2021. 39.