SAR-260301

• CAT Number: I009286
• CAS Number: 1260612-13-2
• Molecular Formula: C19H22N4O3
• Molecular Weight: 354.40
• Purity: ≥95%
• Synonyms: 2-[2-[(2S)-2-methyl-2,3-dihydroindol-1-yl]-2-oxoethyl]-4-morpholin-4-yl-1H-pyrimidin-6-one
• InChI: InChI=1S/C19H22N4O3/c1-13-10-14-4-2-3-5-15(14)23(13)19(25)11-16-20-17(12-18(24)21-16)22-6-8-26-9-7-22/h2-5,12-13H,6-11H2,1H3,(H,20,21,24)/t13-/m0/s1
• InChIKey: UAXHPOBBKRWJGA-ZDUSSCGKSA-N
• SMILES: CC1CC2=CC=CC=C2N1C(=O)CC3=NC(=CC(=O)N3)N4CCOCC4

SAR-260301 is an orally available and selective PI3Kβ inhibitor with an IC50 of 23 nM[1][2].
In the UACC-62 tumor cell line assay, SAR-260301 inhibits pAktS473 with a measured IC50 at 0.06 μM and an estimated IC90 at 2 μM[1]. In MEF-3T3-myr-p110β mechanistic model, SAR260301 inhibits PI3Kβ-dependent proliferation/viability in low serum conditions with an IC50 of 196 nM. In PTEN-deficient human prostate tumor cells, SAR260301 inhibits LNCaP cell proliferation in low and high serum conditions with IC50 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 IC40 values of 6.5 and 3.3 μM for UACC-62 and WM-266.4, respectively, after 4-day treatment[2].
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 (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, 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))[1].

Reference

[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.
 [Content Brief]

[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.
 [Content Brief]