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Voxtalisib (XL-765) is a potent PI3K inhibitor, which has a similar activity toward class I PI3K (IC50s=39, 113, 9 and 43 nM for p110α, p110β, p110γ and p110δ, respectively), also inhibits DNA-PK (IC50=150 nM) and mTOR (IC50=157 nM). Voxtalisib (XL-765) inhibits mTORC1 and mTORC2 with IC50s of 160 and 910 nM, respectively. p110γ|9 nM (IC50)|p110α|39 nM (IC50)|p110δ|43 nM (IC50)|p110β|113 nM (IC50)|mTOR|157 nM (IC50)|mTORC1|160 nM (IC50)|mTORC2|910 nM (IC50)|DNA-PK|150 nM (IC50)

Voxtalisib (XL-765) displays potent inhibitory activity against class I PI3K isoforms p110α, p110β, p110δ, and p120γ, with IC50s of 39, 110, 43, and 9 nM, respectively. The IC50 value for inhibition of PI3Kα by Voxtalisib (XL-765) is determined at various concentrations of ATP, revealing Voxtalisib (XL-765) be an ATP-competitive inhibitor with an equilibrium inhibition constant (Ki) value of 13 nM. Voxtalisib (XL-765) also inhibits mTOR (IC50s of 160 and 910 nM for mTORC1 and mTORC2, respectively) in an immune-complex kinase assay and the PI3K-related kinase DNA-PK (IC50 value of 150 nM). In contrast, Voxtalisib (XL-765) has relatively weak inhibitory activity toward the class III PI3K vacuolar sorting protein 34 (VPS34; IC50 value of ~9.1 μM). Consistent with its inhibitory activity against purified PI3K proteins, SAR245409 inhibits EGF-induced PIP3 production in PC-3 and MCF7 cells with IC50s of 290 and 170 nM, respectively. The ability of Voxtalisib (XL-765) to inhibit phosphorylation of key signaling proteins downstream of PI3K is examined by assessing its effects on EGF-stimulated phosphorylation of AKT and on nonstimulated phosphorylation of S6 in PC-3 cells by cell-based ELISA. Voxtalisib (XL-765) inhibits these activities with IC50s of 250 and 120 nM, respectively. In MCF7 and PC-3 cells, Voxtalisib (XL-765) inhibits proliferation (monitored by BrdUrd incorporation) with IC50s of 1,070 and 1,840 nM, respectively. To further characterize the effects of Voxtalisib (XL-765) on tumor cell growth, an assay monitoring the anchorage-independent growth of PC-3 and MCF7 cells in soft agar over a 14-day period is used. SAR245409 inhibits colony growth with an IC50 value of 270 nM in PC-3 cells and 230 nM in MCF7 cells[2].

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