Background:

BYL719 is a selective PI3Kα inhibitor with IC50 of 5 nM. It has minimal effect on PI3Kβ, γ and δ^[1]. Dysregulation of the PI3K signaling pathway is involved in multiple cancers. Among genes encoding different PI3K catalytic subunits, PIK3CA is mutated in many cancers. Therefore, PI3Kα-specific inhibitor may have anti-tumor activity in PI3Kα mutant cancers with fewer side effects compared to other pan-PI3K inhibitors.

BYL719 exhibited favorable pharmacokinetics and excellent oral bioavailability in animal models. In xenografts using nude mice, it showed dose-dependent effect of tumor inhibition^[1]. It reduced proliferation and induced apoptosis in multiple myeloma cells which have higher expression of PIK3CA. The same study also observed synergistic effect between BYL719 and bortezomib or carfilzomib^[2].

Clinical data suggests a disable safety profile with manageable side effects for BYL719. It also showed preliminary anti-tumor activity as a single agent in cancer patients^[3]. This compound is currently tested in several clinical studies both as single agent and in combination with other agents.

参考文献:
1. Furet P, Guagnano V, Fairhurst RA et al. Discovery of NVP-BYL719 a potent and selective phosphatidylinositol-3 kinase alpha inhibitor selected for clinical evaluation. Bioorg Med Chem Lett 2013; 23: 3741-3748.
2. Azab F, Vali S, Abraham J et al. PI3KCA plays a major role in multiple myeloma and its inhibition with BYL719 decreases proliferation, synergizes with other therapies and overcomes stroma-induced resistance. Br J Haematol 2014; 165: 89-101.
3. Juric D, Argiles G, Burris H et al. Phase I study of BYL719, an alpha-specific PI3K inhibitor, in patients with PIK3CA mutant advanced solid tumors: preliminary efficacy and safety in patients with PIK3CA mutant ER-positive (ER+) metastatic breast cancer (MBC). Cancer Res 2012; 72: P6-10.