A high affinity pan-PI3K binding module supports selective targeted protein degradation of PI3Ka
Ontology highlight
ABSTRACT: Class I phosphoinositide 3-kinases (PI3Ks) control cellular growth, but are also essential in insulin signaling and glucose homeostasis. Pan-PI3K inhibitors thus generate substantial adverse effects, a reality that has plagued drug development against this target class. We present here evidence that a high affinity binding module with the capacity to target all class I PI3K isoforms can facilitate selective degradation of the most frequently mutated class I isoform, PI3Ka, when incorporated into a cereblon-targeted (CRBN) degrader. A systematic proteomics study guided the fine tuning of molecular features to optimize degrader selectivity and potency. Our work resulted in the creation of WJ112-14, a PI3Ka-specific nanomolar degrader that should serve as an important research tool for studying PI3K biology. Given the toxicities observed in the clinic with unselective PI3Ka inhibitors, the results here offer a new approach toward selectively targeting this frequently mutated oncogenic driver.
INSTRUMENT(S): Orbitrap Eclipse, Orbitrap Fusion Lumos
ORGANISM(S): Homo Sapiens (ncbitaxon:9606)
SUBMITTER: Alexander Schmidt
PROVIDER: MSV000093594 | MassIVE | Wed Dec 06 23:21:00 GMT 2023
SECONDARY ACCESSION(S): PXD047599
REPOSITORIES: MassIVE
ACCESS DATA