Discovery and Clinical Proof-of-Concept of RLY-2608, a First-in-Class Mutant-Selective Allosteric PI3Kα Inhibitor That Decouples Antitumor Activity from Hyperinsulinemia.

Autor:	Varkaris A; Mass General Cancer Center and Department of Medicine, Harvard Medical School, Boston, Massachusetts., Pazolli E; Relay Therapeutics, Inc., Cambridge, Massachusetts., Gunaydin H; Relay Therapeutics, Inc., Cambridge, Massachusetts., Wang Q; D. E. Shaw Research, New York, New York., Pierce L; Relay Therapeutics, Inc., Cambridge, Massachusetts., Boezio AA; Relay Therapeutics, Inc., Cambridge, Massachusetts., Bulku A; Relay Therapeutics, Inc., Cambridge, Massachusetts., DiPietro L; Relay Therapeutics, Inc., Cambridge, Massachusetts., Fridrich C; Relay Therapeutics, Inc., Cambridge, Massachusetts., Frost A; Altos Labs, Institute of Science, San Francisco, California.; Department of Biochemistry and Biophysics, University of California San Francisco, San Francisco, California.; California Institute of Quantitative Biosciences (QB3), University of California San Francisco, San Francisco, California., Giordanetto F; D. E. Shaw Research, New York, New York., Hamilton EP; Sarah Cannon Research Institute/Tennessee Oncology, Nashville, Tennessee., Harris K; MGH/Mass General Cancer Center at Danvers, Danvers, Massachusetts., Holliday M; Relay Therapeutics, Inc., Cambridge, Massachusetts., Hunter TL; Relay Therapeutics, Inc., Cambridge, Massachusetts., Iskandar A; Relay Therapeutics, Inc., Cambridge, Massachusetts., Ji Y; Hematology/Oncology, Exeter Hospital, Exeter, New Hampshire., Larivée A; Paraza Pharma, Inc. Montreal, Canada., LaRochelle JR; Relay Therapeutics, Inc., Cambridge, Massachusetts., Lescarbeau A; Relay Therapeutics, Inc., Cambridge, Massachusetts., Llambi F; Relay Therapeutics, Inc., Cambridge, Massachusetts., Lormil B; Mass General Cancer Center and Department of Medicine, Harvard Medical School, Boston, Massachusetts., Mader MM; Relay Therapeutics, Inc., Cambridge, Massachusetts., Mar BG; Relay Therapeutics, Inc., Cambridge, Massachusetts., Martin I; Relay Therapeutics, Inc., Cambridge, Massachusetts., McLean TH; Relay Therapeutics, Inc., Cambridge, Massachusetts., Michelsen K; Relay Therapeutics, Inc., Cambridge, Massachusetts., Pechersky Y; D. E. Shaw Research, New York, New York., Puente-Poushnejad E; Relay Therapeutics, Inc., Cambridge, Massachusetts., Raynor K; Relay Therapeutics, Inc., Cambridge, Massachusetts., Rogala D; Relay Therapeutics, Inc., Cambridge, Massachusetts., Samadani R; Relay Therapeutics, Inc., Cambridge, Massachusetts., Schram AM; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York., Shortsleeves K; Relay Therapeutics, Inc., Cambridge, Massachusetts., Swaminathan S; Relay Therapeutics, Inc., Cambridge, Massachusetts., Tajmir S; MGH Radiology, Harvard Medical School, Boston, Massachusetts., Tan G; Relay Therapeutics, Inc., Cambridge, Massachusetts., Tang Y; Relay Therapeutics, Inc., Cambridge, Massachusetts., Valverde R; Relay Therapeutics, Inc., Cambridge, Massachusetts., Wehrenberg B; Relay Therapeutics, Inc., Cambridge, Massachusetts., Wilbur J; Relay Therapeutics, Inc., Cambridge, Massachusetts., Williams BR; Relay Therapeutics, Inc., Cambridge, Massachusetts., Zeng H; Relay Therapeutics, Inc., Cambridge, Massachusetts., Zhang H; Relay Therapeutics, Inc., Cambridge, Massachusetts., Walters WP; Mass General Cancer Center and Department of Medicine, Harvard Medical School, Boston, Massachusetts., Wolf BB; Relay Therapeutics, Inc., Cambridge, Massachusetts., Shaw DE; D. E. Shaw Research, New York, New York.; Department of Biochemistry and Molecular Biophysics, Columbia University, New York, New York., Bergstrom DA; Relay Therapeutics, Inc., Cambridge, Massachusetts., Watters J; Relay Therapeutics, Inc., Cambridge, Massachusetts., Fraser JS; California Institute of Quantitative Biosciences (QB3), University of California San Francisco, San Francisco, California.; Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, California., Fortin PD; Relay Therapeutics, Inc., Cambridge, Massachusetts., Kipp DR; Relay Therapeutics, Inc., Cambridge, Massachusetts.
Jazyk:	angličtina
Zdroj:	Cancer discovery [Cancer Discov] 2024 Feb 08; Vol. 14 (2), pp. 240-257.
DOI:	10.1158/2159-8290.CD-23-0944
Abstrakt:	PIK3CA (PI3Kα) is a lipid kinase commonly mutated in cancer, including ∼40% of hormone receptor-positive breast cancer. The most frequently observed mutants occur in the kinase and helical domains. Orthosteric PI3Kα inhibitors suffer from poor selectivity leading to undesirable side effects, most prominently hyperglycemia due to inhibition of wild-type (WT) PI3Kα. Here, we used molecular dynamics simulations and cryo-electron microscopy to identify an allosteric network that provides an explanation for how mutations favor PI3Kα activation. A DNA-encoded library screen leveraging electron microscopy-optimized constructs, differential enrichment, and an orthosteric-blocking compound led to the identification of RLY-2608, a first-in-class allosteric mutant-selective inhibitor of PI3Kα. RLY-2608 inhibited tumor growth in PIK3CA-mutant xenograft models with minimal impact on insulin, a marker of dysregulated glucose homeostasis. RLY-2608 elicited objective tumor responses in two patients diagnosed with advanced hormone receptor-positive breast cancer with kinase or helical domain PIK3CA mutations, with no observed WT PI3Kα-related toxicities. Significance: Treatments for PIK3CA-mutant cancers are limited by toxicities associated with the inhibition of WT PI3Kα. Molecular dynamics, cryo-electron microscopy, and DNA-encoded libraries were used to develop RLY-2608, a first-in-class inhibitor that demonstrates mutant selectivity in patients. This marks the advance of clinical mutant-selective inhibition that overcomes limitations of orthosteric PI3Kα inhibitors. See related commentary by Gong and Vanhaesebroeck, p. 204 . See related article by Varkaris et al., p. 227 . This article is featured in Selected Articles from This Issue, p. 201. (©2023 The Authors; Published by the American Association for Cancer Research.)
Databáze:	MEDLINE
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