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Ref Type Abstract
Authors Ermira Pazolli, Randy Kipp, Alessandro Boezio, Hakan Gunaydin, Amanda Iskandar, Matthew Zubrowski, Bret Williams, Kelley Shortsleeves, Alexandre Larivee, Tom McLean, Klaus Michelsen, Hongtao Zeng, Jonathan LaRochelle, Joe Manna, Lucian DiPietro, Mary Mader, Bindu Bennet, Jeremy Wilbur, Qi Wang, Levi Pierce, Iain Martin, James Watters, Pascal Fortin and Donald Bergstrom
Title Discovery and characterization of RLY-2608: The first allosteric, mutant, and isoform-selective inhibitor of PI3Kα
Abstract Text Phosphoinositide 3-kinase alpha (PI3Kα) is the most frequently mutated kinase in solid tumors. Traditionally, the development of PI3Kα inhibitors has focused on the active, or orthosteric site. The therapeutic index of orthosteric inhibitors is limited by the lack of clinically meaningful selectivity for mutant versus wild-type (WT) PI3Kα and off-isoform activity. Alpelisib, the only approved orthosteric PI3Kα inhibitor, is emblematic of the class with toxicity related to inhibition of WT PI3Kα and other PI3K isoforms resulting in sub-optimal inhibition of mutant PI3Kα with reductions in dose intensity and frequent discontinuation. To overcome these limitations, we designed RLY-2608, the first allosteric, mutant, and isoform-selective PI3Kα inhibitor. We solved the full-length cryo-EM structure of PI3Kα, performed long time-scale molecular dynamic simulations to elucidate conformational differences between WT and mutant PI3Kα, and leveraged these insights to enable the design of RLY-2608. RLY-2608 does not compete with orthosteric inhibitors for binding and associates 8x faster with mutant PI3Kα relative to WT. In biochemical assays, RLY-2608 inhibits both kinase domain (H1047R) and helical domain (E542K, and E545K) mutant PI3Kα activity with <10nM potency and 8-12x selectivity relative to WT PI3Kα. RLY-2608 is > 1000-fold selective over the β, δ, and γ PI3K isoforms in biochemical assays and demonstrates exquisite selectivity across a panel of 322 kinases, with no other kinases showing > 50% inhibition. In MCF10A cells engineered to express only mutant or WT PI3Kα, RLY-2608 inhibited phosphorylated AKT (pAKT) in a mutant-selective manner. Furthermore, pAKT and viability were significantly inhibited across a panel of cancer cell lines carrying hotspot PIK3CA mutations. RLY-2608 showed anti-tumor activity in both kinase and helical domain PIK3CA mutant in vivo xenograft models with marked regressions or stasis observed in all models. RLY-2608 was well tolerated, with pharmacodynamic modulation and efficacy observed in a dose dependent manner. Insulin levels measured as an indicator of glucose homeostasis were significantly lower when compared to orthosteric inhibitors, suggesting that RLY-2608 can achieve maximum efficacy by maintaining PI3Kα mutant target coverage throughout the dosing interval with significantly reduced impact on WT PI3Kα. In higher species, dosing of RLY-2608 for 28 days resulted in exposures exceeding mutant PI3Kα cellular PD IC90 throughout the dosing interval without elevated glucose levels or histopathological or ophthalmic findings associated with hyperglycemia. Compared to orthosteric inhibitors, RLY-2608 demonstrates preferential binding and inhibition of mutant PI3Kα, is highly selective across the kinome, and achieves in vivo efficacy without dysregulating glucose homeostasis. These results support clinical investigation of RLY-2608 as a differentiated mechanism for inhibition of oncogenic PI3Kα in patients with PIK3CA mutant tumors.


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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
RLY-2608 RLY-2608 10 1
Drug Name Trade Name Synonyms Drug Classes Drug Description
RLY-2608 RLY 2608|RLY2608 PIK3CA inhibitor 23 RLY-2608 selectively inhibits PIK3CA with higher selectivity and potency against mutant forms of PIK3CA (including PIK3CA E542K, PIK3CA E545K, and PIK3CA H1047R), leading to decreased downstream signaling, and potentially resulting in reduced tumor cell viability and tumor growth (Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P251).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
PIK3CA act mut Advanced Solid Tumor predicted - sensitive RLY-2608 Preclinical - Cell line xenograft Actionable In a preclinical study, RLY-2608 treatment led to inhibition of cell viability in a panel of cancer cell lines harboring PIK3CA hotspot mutations, and led to tumor regression or stasis in cell line xenograft models (Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P251). detail...