Benzinga | Oct 7, 2021 08:51AM EDT

Relay Therapeutics Announces Preclinical Data; Co Says Data Support RLY-2608 As First Known Allosteric Pan-Mutant Selective Inhibitor Of PI3K

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 PI3K? inhibitor.

The data presented at the conference show that in preclinical models, RLY-2608 preferentially binds mutant PI3K? at a novel allosteric site discovered by the Dynamo(tm) platform. Scientists at Relay Therapeutics solved the full-length structure of PI3K?, performed long time-scale molecular dynamic simulations to elucidate differences in motion between wild-type (WT) and mutant PI3K?, and leveraged these insights to enable the design of RLY-2608. In biochemical and cellular assays, RLY-2608 inhibited the three major classes of PI3K? oncogenic mutations (H1047X, E542X and E545X) while sparing WT PI3K?. 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 PI3K? 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 PI3K? inhibition with the first-in-human study anticipated to start in the first half of 2022. RLY-2608 is the lead program of multiple preclinical efforts at Relay Therapeutics to discover and develop mutant selective inhibitors of PI3K?.

RLY-2608 has the potential to address over 100,000 patients per year in the United States, one of the largest patient populations for a precision oncology medicine. Selectivity for all three mutation hot spots (H1047X, E542X and E545X) has the potential to effectively double the addressable patient population compared to selectivity for only H1047X.

"The data shared today provide another proof point that we're developing what we believe to be the first known pan-mutant selective allosteric inhibitor of PI3K?," said Don Bergstrom, M.D., Ph.D., executive vice president of R&D at Relay Therapeutics. "We believe RLY-2608 has the potential to address a significant unmet medical need in a large population and have validated our approach for developing mutant selective inhibitors of PI3K?. RLY-2608 is only the start of our PI3K? efforts, and by leveraging our Dynamo(tm) platform, we plan to build a franchise around this target for the long-term."