Discovery and clinical proof-of-concept of RLY-2608, a first-in-class mutant-selective allosteric PI3Ka inhibitor that decouples anti-tumor activity from hyperinsulinemia

  • Cancer Discov. 2023 Nov 2. doi: 10.1158/2159-8290.CD-23-0944.
Andreas Varkaris  1 ,  Ermira Pazolli  2 ,  Hakan Gunaydin  3 ,  Qi Wang  4 ,  Levi Pierce  2 ,  Alessandro A Boezio  5 ,  Lucian DiPietro  6 ,  Adam Frost  7 ,  Fabrizio Giordanetto  4 ,  Erika P Hamilton  8 ,  Katherine Harris  9 ,  Michael Holliday  5 ,  Tamieka L Hunter  5 ,  Amanda Iskandar  5 ,  Yongli Ji  10 ,  Alexandre Larivée  11 ,  Jonathan R LaRochelle  5 ,  Andre Lescarbeau  5 ,  Fabien Llambi  5 ,  Brenda Lormil  1 ,  Mary M Mader  12 ,  Brenton G Mar  5 ,  Iain Martin  5 ,  Thomas H McLean  5 ,  Klaus Michelsen  5 ,  Yakov Pechersky  13 ,  Erika Puente-Poushnejad  5 ,  Ramin Samadani  5 ,  Alison M Schram  14 ,  Kelley Shortsleeves  5 ,  Sweta Swaminathan  5 ,  Shahein Tajmir  1 ,  Gege Tan  5 ,  Yong Tang  5 ,  Roberto Valverde  5 ,  Bryan Wehrenberg  5 ,  Jeremy Wilbur  5 ,  Bret R Williams  5 ,  Hongtao Zeng  15 ,  W Patrick Walters  5 ,  Beni B Wolf  2 ,  David E Shaw  16 ,  Donald A Bergstrom  5 ,  James Watters  5 ,  James S Fraser  17 ,  Pascal D Fortin  5 ,  D Randal Kipp  5
Affiliations
  • 1. Massachusetts General Hospital, Boston, Massachusetts, United States.
  • 2. Relay Therapeutics (United States), United States.
  • 3. Relay Therapeutics (United States), Cambridge, United States.
  • 4. D. E. Shaw Research, United States.
  • 5. Relay Therapeutics (United States), Cambridge, MA, United States.
  • 6. Relay Therapeutics, Inc., Cambridge, MA, United States.
  • 7. Altos Labs, United States.
  • 8. Sarah Cannon Research Institute and Tennessee Oncology, Nashville, Tennessee, United States.
  • 9. Massachusetts General Hospital, Danvers, Massachusetts, United States.
  • 10. Exeter Hospital, Exeter, NH, United States.
  • 11. Paraza Pharma (Canada), Montreal, Quebec, Canada.
  • 12. Indiana Biosciences Research Institute, Indianapolis, IN, United States.
  • 13. D. E. Shaw Research, New York, United States.
  • 14. Memorial Sloan Kettering Cancer Center, New York, NY, United States.
  • 15. Relay Therapeutics (United States), Cambridge, Massachusetts, United States.
  • 16. D. E. Shaw Research, New York, NY, United States.
  • 17. University of California, San Francisco, San Francsicso, CA, United States.
PMID: 37916956 DOI: 10.1158/2159-8290.CD-23-0944
Abstract

PIK3CA (PI3Ka) 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 PI3Ka inhibitors suffer from poor selectivity leading to undesirable side effects, most prominently hyperglycemia due to inhibition of wild-type (WT) PI3Ka. Here, we used molecular dynamics simulations and cryo-electron microscopy to identify an allosteric network that provides an explanation for how mutations favor PI3Ka 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 PI3Ka. 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 PI3Ka-related toxicities.

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