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Mutant p53 (mutp53) functions as an oncogene by promoting metastasis and drug resistance, which is referred to as gain of function (GOF). Accumulation of mutp53 in cancer cells is crucial for their GOF activity while depletion of mutp53 significantly inhibits cancer progression. Hence, targeting mutp53 for degradation is a promising approach for cancer therapy. We recently demonstrated that DNAJA1 binds to and protects unfolded type of mutp53 from degradation. Targeting DNAJA1 could, therefore, inhibit cancer progression by inducing degradation of unfolded mutp53. However, no inhibitors of DNAJA1 or JDPs/HSP40 are clinically available. To identify potential DNAJA1 inhibitors, we performed in-silico docking using a natural compound library with the J-domain of DNAJA1 as a probe. After validation, we identified a plumbagin derivative that decreased the protein levels of unfolded mutp53. CETSA studies confirmed intracellular binding of this compound with DNAJA1. We furthermore synthesized several analogs of this compound and focused on a compound, namely PLTFBH, as it efficiently reduced the protein levels of both DNAJA1 and unfolded mutp53. PLTFBH showed nonspecific cytotoxicity in a manner independent of DNAJA1 or mutp53. However, it showed specific inhibition of cancer cell migration dependent on DNAJA1 and mutp53, since filopodia formation and migration of cells lacking DNAJA1 or mutp53 were minimally affected by PLTFBH. These findings could pave the way toward discovery of a promising targeted therapy for various cancer conditions.
Alalem, Mohamed A.A.; Ranjan, Atul; Yamamoto, Satomi; Kaida, Atsushi; Parrales, Alejandro; Farooki, Sana; Anant, Shrikant; and Iwakuma, Tomoo, "Mutant P53 Degradation By Potential HSP40/J-Domain Protein Inhibitors Derived From A Natural Compound" (2021). Research at Children's Mercy Month 2021. 11.
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