DNAJA1- and conformational mutant p53-dependent inhibition of cancer cell migration by a novel compound identified...

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• Cancers often rely on oncogenic missense mutant p53 (mutp53) for survival.
• DNAJA1, a heat shock protein 40 (HSP40) family member, stabilizes mutp53, preventing its degradation and promoting oncogenic activity.
• Targeted depletion of mutp53 is challenging due to a lack of established strategies and available HSP40/J-domain protein (JDP) inhibitors.

Purpose of the Study:

• To identify compounds that bind to DNAJA1 and induce the degradation of conformational mutp53.
• To evaluate the efficacy of identified compounds in inhibiting cancer cell migration.

Main Methods:

• An in silico docking study of approximately 10 million compounds from the ZINC database against the DNAJA1 J-domain.
• In vitro validation of compound A11's effects on DNAJA1 and mutp53 levels, cancer cell migration, and filopodia formation.
• Assessment of A11's mechanism of action using mutant DNAJA1 expressing cells.

Main Results:

• Compound 7-3 and its analogue A11 were identified as DNAJA1 binders.
• A11 effectively reduced DNAJA1 and conformational mutp53 levels, while minimally affecting wild-type p53 and DNA-contact mutp53.
• A11 suppressed cancer cell migration and filopodia formation in a DNAJA1 and conformational mutp53-dependent manner.
• Mutant DNAJA1 cells were insensitive to A11's depletion effects and migration inhibition.

Conclusions:

• A11 is the first characterized HSP40/JDP inhibitor that depletes DNAJA1 and subsequently conformational mutp53.
• A11 inhibits cancer cell migration by targeting the DNAJA1-mutp53 interaction.
• A11 represents a promising novel therapeutic agent for cancers expressing conformational mutp53.