The phosphoinositide 3-kinase (PI3K) pathway activation plays a major role in cancer. The PI3K-AKT pathway is one of the most important signaling networks in cancer. Activation of PI3K-AKT pathway plays a significant role in melanoma. PI3K family divides into three classes (I, II, and III). In melanoma, PI3K pathway is major mediator of tumorigenic signaling. Thus, researchers develop PI3Kβ-selective kinase inhibitors for the treatment of PTEN-deficient malignancies. Of these, SAR-260301 is an orally bioavailable PI3Kβ-selective inhibitor for melanoma treatment.

In this study, Hélène Bonnevaux, et al developed a program to discover PI3Kβ-selective kinase inhibitors. Fortunately, they found and identified SAR-260301 as a PI3Kβ-selective nhibitor. Especially, SAR-260301 is a potent ATP-competitive PI3Kβ inhibitor. Particularly, SAR-260301 inhibits PI3Kβ lipid kinase activity with an IC50 of 52 nM at 100 μM ATP. Moreover, SAR-260301 is a selective PI3Kβ kinase inhibitor in biochemical assays. SAR-260301 shows moderate inhibitory activity against PI3Kδ (7.8-fold selectivity) and VPS34 (3.5-fold selectivity). Besides, SAR-260301 inhibits PI3Kβ with a potency 26-fold higher than PI3Kδ (IC50 32 vs 823 nM), shows lower potency against PI3Kα (IC50 2,825 nM) and no inhibitory activity against PI3Kγ or VPS34 (≤30% inhibition at 3 or 10 μM). In addition to above effects, SAR-260301 also inhibits the PI3K pathway preferentially in PTEN-deficient cells.

SAR-260301 has moderate antitumor activity as a single agent. SAR-260301 demonstrates significant in vivo activity in a UACC-62 xenograft model in mice. Researchers demonstrate that SAR-260301 blocks PI3K pathway signaling preferentially in PTEN-deficient human tumor models. SAR-260301 has synergistic antitumor activity when combined with Vemurafenib (BRAF inhibitor) or Selumetinib (MEK inhibitor) in PTEN-deficient/BRAF-mutated human melanoma tumor models.

Bonnevaux H, et al. Concomitant Inhibition of PI3Kβ and BRAF or MEK in PTEN-Deficient/BRAF-Mutant Melanoma Treatment: Preclinical Assessment of SAR260301 Oral PI3Kβ-Selective Inhibitor. Mol Cancer Ther. 2016 Jul;15(7):1460-71.