SAR-260301

SAR-260301 is an orally available and selective PI3Kβ inhibitor with an IC 50 of 23 nM In Vitro In the UACC-62 tumor cell line assay, SAR-260301 inhibits pAktS473 with a measured IC 50 at 0.06 μM and an estimated IC 90 at 2 μM. In MEF-3T3-myr-p110β mechanistic model, SAR260301 inhibits PI3Kβ-dependent proliferation/viability in low serum conditions with an IC 50 of 196 nM. In PTEN-deficient human prostate tumor cells, SAR260301 inhibits LNCaP cell proliferation in low and high serum conditions with IC 50 values of 2.9 and 5.0 μM, respectively, after 4-day treatment, whereas it is inactive in these conditions in PC3 cells at concentrations up to 10 μM, despite target engagement. After prolonged treatment, SAR260301 at 3 or 10 μM inhibits PC3 cell proliferation in low serum conditions, with a cytostatic effect achieved for 14 days, despite some cell death induction observed at 10 μM. SAR260301 also leads to antitumor activities in PTEN-deficient/ BRAF -mutant human melanoma cells, inhibiting cell proliferation with IC 40 values of 6.5 and 3.3 μM for UACC-62 and WM-266.4, respectively, after 4-day treatment. MCE has not independently confirmed the accuracy of these methods. They are for reference only. In Vivo SAR-260301 displays antitumor efficacy in human PTEN-deficient melanoma models in mice as a single agent. SAR-260301 treatment leads to a statistically significant tumor growth inhibition as measured by a ΔT/ΔC of 39% (p = 0.054 versus control mice) on day 15 post-tumor implantation. SAR-260301 is well tolerated at the active dose, with no sign of toxicity and no body weight loss. Oral administration of SAR-260301 reveals sustained target inhibition (≥50%) of pAkt-S473 for at least 7 h. SAR-260301 has moderate terminal elimination half-life (t 1/2 =0.87 h, 1.4 h, 2.5 h, 0.87h, 6.9 h and 4.5 h for female SCID mice (3 mg/kg, iv), mice (10 mg/kg, po), mice (100 mg/kg, po), female nude rats (3 mg/kg, iv), rat (10 mg/kg, po), male beagle dogs (10 mg/kg, po)) . MCE has not independently confirmed the accuracy of these methods. They are for reference only. Cell Assay Cell proliferation is measured by quantifying intracellular ATP using CellTiter-Glo kit. Cells seeded into 96-well black microplates in complete medium, are treated with single or combined agents (e.g., SAR260301) 0.3 nM-30 μM (0.1% DMSO final concentration) for 96 hours. MCE has not independently confirmed the accuracy of these methods. They are for reference only. Form:Solid IC50& Target:PI3Kβ 23 nM (IC 50 ) PI3Kδ 468 nM (IC 50 ) PI3Kα 1539 nM (IC 50 ) PI3Kγ 10000 nM (IC 50 ) Vps34 183 nM (IC 50 ) PI3KC2γ 3812 nM (IC 50 ) pAkt 49 nM (IC 50 ) DNA-PK 2000 nM (IC 50 )

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