| Description | SAR-260301 is an orally available and selective inhibitor of PI3Kβ (IC50: 23 nM). |
| In vitro | SAR-260301 inhibits pAktS473 (a measured IC50: 0.06 μM and an estimated IC90: 2 μM), in the UACC-62 tumor cell line assay. SAR260301 inhibits PI3Kβ-dependent proliferation/viability in low serum conditions (IC50: 196 nM), in the MEF-3T3-myr-p110β mechanistic model. SAR260301 inhibits LNCaP cell proliferation in low and high serum conditions (IC50: 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). SAR260301 also leads to antitumor activities in PTEN-deficient/BRAF-mutant human melanoma cells, inhibiting cell proliferation (IC40: 6.5 and 3.3 μM for UACC-62 and WM-266.4, respectively, after 4-day treatment). 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 [2]. |
| In vivo | SAR-260301 is well tolerated at the active dose, with no sign of toxicity and no bodyweight loss. 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(p.o.) reveals sustained target inhibition (≥50%) of pAkt-S473 for at least 7 h. SAR-260301 has moderate terminal elimination half-life (t1/2=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, p.o.), mice (100 mg/kg, p.o.), female nude rats (3 mg/kg, iv), rat (10 mg/kg, p.o.), male beagle dogs (10 mg/kg, p.o.)) [1]. |
| Target activity | PI3Kγ:10000 nM, pAkt:49 nM, PI3Kα:1539 nM, DNA-PK:2000 nM, PI3Kβ:23 nM, PI3KC2γ:3812 nM, VPS34:183 nM, PI3Kδ:468 nM |
| molecular weight | 354.4 |
| Molecular formula | C19H22N4O3 |
| CAS | 1260612-13-2 |
| Storage | Powder: -20°C for 3 years | In solvent: -80°C for 1 year |
| Solubility | DMSO: 125 mg/mL (352.71 mM), Sonication is recommended. |
| References | 1. Certal V, et al. Discovery and optimization of pyrimidone indoline amide PI3Kβ inhibitors for the treatment of phosphatase and tensin homologue (PTEN)-deficient cancers. J Med Chem. 2014 Feb 13;57(3):903-20. 2. 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. |