PI3Kα is one of the most commonly mutated oncogenes in cancer. PI3Kα can be activated by oncogenic point mutations in PI3Kα gene. The three most common mutations of PI3Kα are H1047R, E542K and E545K. Mutation of PI3KαH1047R in a mouse model has induced breast cancer tumorigenesis and is also associated with drug resistance to HER2-targeting agents in breast cancer. PI3Kα is mutated in up to 38% of breast cancer cases.
PI3Kα is a clinically proven target in metastatic breast cancer patients harboring mutations in this oncogene. First-generation PI3Kα inhibitors are only 1-5X selective for the mutant enzyme compared to the wild type, which results in on-target toxicity (including hyperglycemia, rash, stomatitis, and diarrhea) that limits the potential to dose to higher and potentially more active exposures. This safety profile may also impede advancement into the adjuvant setting.
OnKure believes that a high degree of mutation-selectivity is required to drive optimal efficacy without burdening patients with the toxic side effects of targeting the wild-type enzyme. A highly selective mutant PI3Kα may achieve much greater activity and tolerability by sparing on-target inhibition of the wild-type enzyme and enabling greater and longer target coverage by being able to dose to exposures above those that can be achieved by less-selective molecules.
Program/TargetProg/Tgt | Initial IndicationInd | DiscoveryDiscov | PreclinicalPreclin | ClinicalClin | Program StatusStatus | |
|---|---|---|---|---|---|---|
OKI-355 | ||||||
Vascular Anomalies | ||||||
OKI-355 PI3KαPAN mutant-selective inhibitor | Vascular Anomalies | IND Enabling Studies Ongoing | ||||
OKI-345 | ||||||
Breast Cancer | ||||||
OKI-345 PI3KαPAN mutant-selective inhibitor | Breast Cancer | IND Enabling Studies Ongoing | ||||
OnKure selects its targets based on the following criteria:
