Mutant p53 Depletion by Novel Inhibitors for HSP40/J-Domain Proteins Derived from the Natural Compound Plumbagin

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• Missense mutant p53 (mutp53) accumulation drives cancer malignancy.
• DNAJA1, an HSP40/J-domain protein, stabilizes conformational mutp53 against proteasomal degradation.
• Targeting DNAJA1 is a potential therapeutic strategy for cancers reliant on mutp53.

Purpose of the Study:

• To identify small molecule inhibitors of DNAJA1.
• To evaluate the efficacy of identified compounds in reducing mutp53 levels and inhibiting cancer cell migration.
• To explore the mechanism of action and specificity of the lead compound.

Main Methods:

• In silico molecular docking using a natural compound library.
• Treatment of cancer cells with identified compounds (PLIHZ, PLTFBH).
• Western blotting to assess protein levels (DNAJA1, mutp53, wtp53).
• Cell migration assays.
• Analysis of HSP40/JDPs and DNAJA1 mutants.

Main Results:

• PLIHZ, a plumbagin derivative, was identified as a potential DNAJA1 binder.
• PLIHZ and PLTFBH reduced DNAJA1 and conformational mutp53 levels, with minimal effect on DNA contact mutp53 and wild-type p53.
• PLTFBH specifically inhibited migration of cancer cells with conformational mutp53.
• PLTFBH depleted various HSP40/JDPs but not DNAJA1 mutants lacking specific tyrosine residues.
• Depletion of DNAJA1 or mutp53 attenuated PLTFBH's effect on cell migration.

Conclusions:

• PLIHZ and PLTFBH are promising compounds for targeting DNAJA1 and reducing oncogenic mutp53.
• PLTFBH demonstrates specific anti-migratory effects in cancers harboring conformational mutp53.
• PLTFBH acts as a potential inhibitor of multiple HSP40/JDPs, suggesting broader therapeutic applications.