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

Author:

Varkaris Andreas1ORCID,Pazolli Ermira2ORCID,Gunaydin Hakan2ORCID,Wang Qi3ORCID,Pierce Levi2ORCID,Boezio Alessandro A.2ORCID,Bulku Artemisa2,DiPietro Lucian2ORCID,Fridrich Cary2,Frost Adam456ORCID,Giordanetto Fabrizio3ORCID,Hamilton Erika P.7ORCID,Harris Katherine8ORCID,Holliday Michael2ORCID,Hunter Tamieka L.2ORCID,Iskandar Amanda2ORCID,Ji Yongli9ORCID,Larivée Alexandre10ORCID,LaRochelle Jonathan R.2ORCID,Lescarbeau André2ORCID,Llambi Fabien2ORCID,Lormil Brenda1ORCID,Mader Mary M.2ORCID,Mar Brenton G.2ORCID,Martin Iain2ORCID,McLean Thomas H.2ORCID,Michelsen Klaus2ORCID,Pechersky Yakov3ORCID,Puente-Poushnejad Erika2ORCID,Raynor Kevin2,Rogala Dipali2,Samadani Ramin2ORCID,Schram Alison M.11ORCID,Shortsleeves Kelley2ORCID,Swaminathan Sweta2ORCID,Tajmir Shahein12ORCID,Tan Gege2ORCID,Tang Yong2ORCID,Valverde Roberto2ORCID,Wehrenberg Bryan2ORCID,Wilbur Jeremy2ORCID,Williams Bret R.2ORCID,Zeng Hongtao2ORCID,Zhang Hanmo2,Walters W. Patrick1ORCID,Wolf Beni B.2ORCID,Shaw David E.313ORCID,Bergstrom Donald A.2ORCID,Watters James2ORCID,Fraser James S.614ORCID,Fortin Pascal D.2ORCID,Kipp D. Randal2ORCID

Affiliation:

1. 1Mass General Cancer Center and Department of Medicine, Harvard Medical School, Boston, Massachusetts.

2. 2Relay Therapeutics, Inc., Cambridge, Massachusetts.

3. 3D. E. Shaw Research, New York, New York.

4. 4Altos Labs, Institute of Science, San Francisco, California.

5. 5Department of Biochemistry and Biophysics, University of California San Francisco, San Francisco, California.

6. 6California Institute of Quantitative Biosciences (QB3), University of California San Francisco, San Francisco, California.

7. 7Sarah Cannon Research Institute/Tennessee Oncology, Nashville, Tennessee.

8. 8MGH/Mass General Cancer Center at Danvers, Danvers, Massachusetts.

9. 9Hematology/Oncology, Exeter Hospital, Exeter, New Hampshire.

10. 10Paraza Pharma, Inc. Montreal, Canada.

11. 11Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.

12. 12MGH Radiology, Harvard Medical School, Boston, Massachusetts.

13. 13Department of Biochemistry and Molecular Biophysics, Columbia University, New York, New York.

14. 14Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, California.

Abstract

Abstract 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 article by Varkaris et al.

Publisher

American Association for Cancer Research (AACR)

Subject

Oncology

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