ONCOLOGY: PI3Kα
Our pan-mutant PI3Kα inhibitor program targets kinase- and helical-driver mutations
The phosphoinositide 3-kinase alpha (PI3Kα) plays a critical role in cell growth, metabolism, and survival. Mutations in the PIK3CA gene, which encodes the catalytic subunit of the PI3Kα protein, are present in approximately 17% of all solid tumors, making PIK3CA one of the most common genetic drivers in cancer. Specifically, hotspot mutations in the kinase (H1047X) and helical (E545X, E542X) domains drive uncontrolled pathway activation that results in cancer formation.
Approved and current late-stage clinical PI3Kα inhibitors lack sufficient selectivity for these mutations over healthy, wild-type PI3Kα. This lack of precision can lead to treatment-limiting side effects that reduce patient tolerability and shorten progression-free survival. We are advancing wild-type sparing, pan-mutant PI3Kα inhibitors because improved selectivity is expected to translate into a superior clinical profile. By sparing healthy tissue, our approach is designed to enable higher dosing and longer treatment durations, while facilitating more effective combination regimens with chemotherapy, immunotherapies, and other targeted agents.
Boron chemistry creates novel chemical matter in a crowded PI3Kα inhibitor space, offering a clear intellectual property advantage in a target class with numerous competitors.
Developing a potentially best-in-class, mutant-selective, wild-type sparing PI3Kα inhibitor
Preclinical highlights
In vivo efficacy comparable to that of alpelisib.
Efficacious doses do not trigger toxicities associated with inhibiting wild-type PI3Kα.
Our goal in targeting PI3Kα is to bring forward a best-in-class, wildtype sparing, mutant-selective PI3Kα inhibitor that can expand treatment options into areas where they are most limited.
Cancers with the highest prevalence of PIK3CA mutations
| Cancer type | Frequency of PIK3CA mutations |
|---|---|
| Breast | ~35% |
| Endometrial | ~25% |
| Colorectal | ~20% |
Boron’s unique chemistry allows access to an allosteric binding site on PI3Kα that conventional chemistries have struggled to reach, delivering a best-in-class profile with enhanced mutant selectivity and improved tolerability.
Our next generation, boron-based pan-mutant inhibitors are designed to achieve 10x–100x selectivity over wild-type PI3Kα while maintaining potency across the most clinically significant oncogenic mutations.