7 minute read
Feb. 5, 2024

RLY-2608: An Allosteric Pan-Mutant-Selective PI3Kα Inhibitor Without Hyperglycemia in Preclinical Models


oral allosteric pan-mutant isoform-selective PI3Kα inhibitor Ph. I for PIK3CA mutant cancers from DEL screen for mutant-specific allosteric inhibitors Cancer Discov., November 2023 D.E. Shaw Research / Relay Therapeutics


RLY-2608 is an oral, mutant-selective PI3Kα allosteric inhibitor discovered by Relay Therapeutics that targets a cryptic pocket near the ATP-binding site. Current FDA-approved PI3Kα modulator (alpelisib) and a clinically advanced molecule (inavolisib) are limited by their off-target toxicities associated with the inhibition of WT PI3Kα, leading to significant side effects, including hyperglycemia and rash. RLY-2608 is currently being evaluated in a Ph. I clinical trial as a single agent and in combination with fulvestrant for HR+/HER2- breast cancer treatment. This article details the discovery strategy for RLY-2608, its notable mechanism mutant selectivity, how it compares to other molecules, preclinical activity, recent clinical developments, and more.



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