Targeting the PP2A phosphatome with structure-based drug design and a selective heterotrimeric binding pocket.
EMSL Project ID
51062
Abstract
A major serine/threonine phosphatase, Protein Phosphatase 2A (PP2A), is responsible for the majority of cellular phosphatase activity under physiologic conditions and is dysregulated in an array of human diseases including neurodegeneration, cardiovascular disease, diabetes, and cancer. PP2A is a multi-subunit phosphatase minimally composed of a scaffolding A and a catalytic C subunit. The ability of PP2A to dephosphorylate a vast repertoire of distinct protein substrates is regulated by over 40 specificity determining regulatory “B” subunits that compete for assembly to form active PP2A heterotrimers. Selective enrichment of specific B-subunits within the heterogenous pool of active PP2A enzymes provides the opportunity to manipulate a diverse set of substrates that are regulated by phosphorylation events.The goal of this project is to develop small molecule activators of PP2A capable of directing specific substrate directed catalysis. Screening of potential small molecule PP2A activators will be strategically designed to identify compounds capable of stabilizing specific PP2A heterotrimers, targeted at the unique trimeric complex interface, to selectively enhance target dephosphorylation. As a proof of concept, we have solved the structure of the B56alpha containing PP2A heterotrimeric complex bound with a lead small molecule activator, DT-061. Administration of DT-061 results in stabilization of B56alpha-PP2A complexes and subsequent PP2A-mediated dephosphorylation of the well-known oncoprotein c-MYC to reduce tumor volume in lung cancer xenografts. Importantly, this target specificity is achieved through the ability of DT-061 to bind at the trimeric protein interface unique to B56alpha containing complexes. These data provide the foundation to develop second-generation, structure-based molecules to better bind to B56?-PP2A complexes for treating cancer and with fewer off-target effects. Moreover, we aim to use a similar strategy to target other B-subunit containing PP2A complexes, through selective stabilization of unique regulatory B subunit containing PP2A enzymes capable of targeting other pathogenic hyperphosphorylated substrates.
Project Details
Start Date
2019-10-15
End Date
2021-03-17
Status
Closed
Released Data Link
Team
Principal Investigator
Team Members