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Relay Therapeutics Announces Preclinical Data that Support RLY-2608 as the First Known Allosteric Pan-Mutant Selective Inhibitor of PI3Kα
RLY-2608 preferentially binds mutant PI3Kα at a novel allosteric site discovered by the Dynamo™ platform Preclinically, achieved tumor regressions in vivo
About this update from Relay Therapeutics, Inc.
[{"type":"text","content":"RLY-2608 preferentially binds mutant PI3Kα at a novel allosteric site discovered by the Dynamo™ platform Preclinically, achieved tumor regressions in vivo with significantly reduced impact on glucose metabolism compared to active site inhibitors RLY-2608’s pan-mutant inhibition has the potential to address over 100,000 patients per year in the U.S. CAMBRIDGE, Mass., Oct. 07, 2021 (GLOBE NEWSWIRE) -- Relay Therapeutics, Inc. (Nasdaq: RLAY), a clinical-stage precision medicine company transforming the drug discovery process by combining leading-edge computational and experimental technologies, today shared preclinical data at the virtual AACR-NCI-EORTC Molecular Targets Conference for RLY-2608, the first allosteric, pan-mutant (H1047X, E542X and E545X) and isoform-selective PI3Kα inhibitor. The data presented at the conference show that in preclinical models, RLY-2608 preferentially binds mutant PI3Kα at a novel allosteric site discovered by the Dynamo™ platform. Scientists at Relay Therapeutics solved the full-length structure of PI3Kα, performed long time-scale molecular dynamic simulations to elucidate differences in motion between wild-type (WT) and mutant PI3Kα, and leveraged these insights to enable the design of RLY-2608. In biochemical and cellular assays, RLY-2608 inhibited the three major classes of PI3Kα oncogenic mutations (H1047X, E542X and E545X) while sparing WT PI3Kα. The data further suggest that RLY-2608 is also highly selective against other PI3K family members and exquisitely selective across the kinome. The data suggest that projected clinically relevant doses of RLY-2608 achieved tumor regression in PIK3CA mutant in vivo xenograft models representing H1047R and E545K mutations with significantly reduced impact on glucose metabolism compared to non-mutant selective active site inhibitors. In higher species, dosing of RLY-2608 resulted in exposures exceeding 90% inhibition of mutant PI3Kα in cells without resulting in elevated glucose levels or histopathological changes associated with dysregulation of glucose metabolism that are seen with non-mutant selective inhibitors. These results support advancement of RLY-2608 into clinical development as a differentiated mechanism of mutant PI3Kα inhibition with the first-in-human study anticipated to start in the first half of 2022. RLY-2608 is the lead program of mult...