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    DRUG CLASS:

    pan-mutant PIK3CA-selective inhibitor

    Related drugs:
    5ms
    mTOR variants activation discovers PI3K-like cryptic pocket, expanding allosteric, mutant-selective inhibitor designs. (PubMed, bioRxiv)
    The cryptic pocket created by disrupted α-packing coincides with the allosteric pocket in PI3Kα can be harmoniously fitted by the PI3Kα allosteric inhibitor RLY-2608, suggesting that analogous drugs designed based on RLY-2608 can restore the packed α-structure, resulting in mTOR inactive conformation. Our results exemplify that knowledge of detailed kinase activation mechanisms can inform innovative allosteric inhibitor development.
    Journal
    |
    PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) • PI3K (Phosphoinositide 3-kinases)
    |
    zovegalisib (RLY-2608)
    5ms
    ReDiscover: First-in-Human Study of Mutant-selective PI3Kα Inhibitor, RLY-2608, as a Single Agent in Patients With Advanced Solid Tumors and in Combination With Endocrine Therapy +/- a CDK4/6 or CDK4 Inhibitor in Patients With Advanced Solid Tumors or Advanced Breast Cancer (clinicaltrials.gov)
    P1, N=930, Recruiting, Relay Therapeutics, Inc. | Trial completion date: Aug 2026 --> Apr 2027 | Trial primary completion date: Dec 2025 --> Apr 2027
    Trial completion date • Trial primary completion date • First-in-human
    |
    HER-2 (Human epidermal growth factor receptor 2) • PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) • BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset)
    |
    HER-2 negative • PIK3CA mutation
    |
    Ibrance (palbociclib) • Kisqali (ribociclib) • fulvestrant • zovegalisib (RLY-2608) • atirmociclib (PF-07220060)
    7ms
    In Silico Discovery of a Novel Potential Allosteric PI3Kα Inhibitor Incorporating 3-(2-Chloro-5-fluorophenyl)isoindolin-1-one to Target Head and Neck Squamous Cell Carcinoma. (PubMed, Biology (Basel))
    Compared to ATP-competitive PI3Kα inhibitors such as Alpelisib, the allosteric inhibitor RLY-2608 exhibits enhanced selectivity for mutant PI3Kα while minimizing the inhibition of wild-type PI3Kα, thereby reducing side effects such as hyperglycemia. Through integrated approaches, including molecular docking studies, target validation, druggability evaluation, molecular dynamics simulations, and metabolic pathway and metabolite analyses, we successfully identified a promising novel allosteric PI3Kα inhibitor, H-18 (3-(2-chloro-5-fluorophenyl)isoindolin-1-one). H-18 has not been previously reported as a PI3Kα inhibitor, and provides an excellent foundation for subsequent lead optimization, offering a significant starting point for the development of more potent PI3Kα allosteric inhibitors.
    Journal • IO biomarker
    |
    PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha)
    |
    PIK3CA mutation
    |
    Piqray (alpelisib) • zovegalisib (RLY-2608)
    7ms
    ReDiscover-2: Phase 3 Study of RLY-2608 + Fulvestrant vs Capivasertib + Fulvestrant as Treatment for Locally Advanced or Metastatic PIK3CA-mutant HR+/HER2- Breast Cancer (clinicaltrials.gov)
    P3, N=540, Recruiting, Relay Therapeutics, Inc. | Not yet recruiting --> Recruiting
    Enrollment open
    |
    fulvestrant • Truqap (capivasertib) • zovegalisib (RLY-2608)
    9ms
    ReDiscover-2: Phase 3 Study of RLY-2608 + Fulvestrant vs Capivasertib + Fulvestrant as Treatment for Locally Advanced or Metastatic PIK3CA-mutant HR+/HER2- Breast Cancer (clinicaltrials.gov)
    P3, N=540, Not yet recruiting, Relay Therapeutics, Inc.
    New P3 trial
    |
    fulvestrant • Truqap (capivasertib) • zovegalisib (RLY-2608)
    9ms
    First-in-Human Study of RLY-5836 in Advanced Breast Cancer and Other Solid Tumors (clinicaltrials.gov)
    P1, N=41, Completed, Relay Therapeutics, Inc. | Active, not recruiting --> Completed | N=265 --> 41
    Trial completion • Enrollment change
    |
    HER-2 (Human epidermal growth factor receptor 2) • PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha)
    |
    HER-2 negative • PIK3CA mutation
    |
    Ibrance (palbociclib) • Verzenio (abemaciclib) • Kisqali (ribociclib) • fulvestrant • RLY-5836
    10ms
    RLY-2608-201: A Phase 2 Study of Mutant-selective PI3Kα Inhibitor, RLY-2608, in Adults and Children With PIK3CA Related Overgrowth Spectrum and Malformations Driven by PIK3CA Mutation (clinicaltrials.gov)
    P2, N=280, Recruiting, Relay Therapeutics, Inc. | Not yet recruiting --> Recruiting
    Enrollment open
    |
    zovegalisib (RLY-2608)
    12ms
    First-in-Human Study of RLY-5836 in Advanced Breast Cancer and Other Solid Tumors (clinicaltrials.gov)
    P1, N=265, Active, not recruiting, Relay Therapeutics, Inc. | Trial completion date: Jul 2024 --> May 2025 | Trial primary completion date: Jun 2024 --> Mar 2025
    Trial completion date • Trial primary completion date
    |
    HER-2 (Human epidermal growth factor receptor 2) • PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha)
    |
    HER-2 negative • PIK3CA mutation
    |
    Ibrance (palbociclib) • Verzenio (abemaciclib) • Kisqali (ribociclib) • fulvestrant • RLY-5836
    1year
    ReDiscover: First-in-Human Study of Mutant-selective PI3Kα Inhibitor, RLY-2608, As a Single Agent in Advanced Solid Tumor Patients and in Combination with Fulvestrant in Patients with Advanced Breast Cancer (clinicaltrials.gov)
    P1, N=890, Recruiting, Relay Therapeutics, Inc. | N=400 --> 890
    Enrollment change
    |
    HER-2 (Human epidermal growth factor receptor 2) • PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) • BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset)
    |
    HER-2 negative • PIK3CA mutation
    |
    Ibrance (palbociclib) • Kisqali (ribociclib) • fulvestrant • zovegalisib (RLY-2608) • atirmociclib (PF-07220060)
    1year
    A Phase 2 Study of Mutant-selective PI3Kα Inhibitor, RLY-2608, in Adults and Children with PIK3CA Related Overgrowth Spectrum and Malformations Driven by PIK3CA Mutation (clinicaltrials.gov)
    P2, N=280, Not yet recruiting, Relay Therapeutics, Inc.
    New P2 trial
    |
    zovegalisib (RLY-2608)
    1year
    mTOR Variants Activation Discovers PI3K-like Cryptic Pocket, Expanding Allosteric, Mutant-Selective Inhibitor Designs. (PubMed, J Chem Inf Model)
    The cryptic pocket created by disrupted α-packing coincides with the allosteric pocket in PI3Kα can be harmoniously fitted by the PI3Kα allosteric inhibitor RLY-2608, suggesting that analogous drugs designed based on RLY-2608 can restore the packed α-structure, resulting in mTOR inactive conformation. Our results exemplify that knowledge of detailed kinase activation mechanisms can inform innovative allosteric inhibitor development.
    Journal
    |
    PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) • PI3K (Phosphoinositide 3-kinases)
    |
    zovegalisib (RLY-2608)