Modulation of CIP2A dimerization and protein stability via druggable pocket

Abstract

Cancerous inhibitor of PP2A (CIP2A) supports malignant growth across several cancer types. CIP2A is also a synthetic lethal therapy target for BRCA-mutant cancers. In addition, CIP2A causes Alzheime[r]s disease (AD) phenotype in mice. However, it is not dispensable for normal development and growth. Therefore, CIP2A is very lucrative therapy target in cancer and AD. So far it has been unclear whether the CIP2A protein harbors any druggable pockets amenable to targeting by small molecules. Here we discover a druggable pocket adjacent to the homodimerization domain of CIP2A. Mutagenesis demonstrates that pocket impacts CIP2A homodimerization, PP2A interaction, and full-length CIP2A protein stability in cancer cells. Further, we identify Gambogenic acid (GNA) as a tool compound that directly binds to CIP2A pocket region. GNA and its derivative Gambogic acid dissociate CIP2A homodimer in vitro and cause CIP2A destabilization in cellulo. The pocket contributes to the impact of GNA on homodimerization based on the protein fragment and mutagenesis analysis. These results identify structural vulnerability on CIP2A and may facilitate development of targeted CIP2A inhibitors with broad disease applicability.