SAR260301

本公司产品仅用于科研实验，不得用于人体或动物的临床与诊断

SAR260301 (SAR-260301, SAR 260301) 是一种有效的、选择性的、ATP 竞争性 PI3Kβ 抑制剂，在 TR-FRET 测定中 IC50 为 52 nM。

SAR260301 (SAR-260301, SAR 260301) is a potent, selective, ATP-competitive PI3Kβ inhibitor with IC50 of 52 nM in TR-FRET assays, with littile to no actiivty against PI3Kα/γ/δ (IC50=1,869/>10,000/403 nM, respectively); does not inhibit mTOR (IC50 >10 uM, the only other kinase inhibited by SAR260301 was VPS34 lipid kinase (IC50=180 nM) in a panel of >400 kinases; inhibits AKT-Ser473 phosphorylation in cellular assays with IC50 of 32 nM, 26-fold, 88-fold, >94-fold, and >313-fold more potently than PI3Kδ, PI3Kα, PI3Kγ, and VPS34, respectively; inhibits the PI3K pathway preferentially in PTEN-deficient cells, synergizes with MAPK pathway inhibitors to inhibit growth of PTEN-deficient and BRAF-mutant melanoma cells in vitro and in vivo.Blood Cancer Discontinued.

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. 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.

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)).

SAR-260301 | SAR 260301

PI3K/Akt/mTOR signaling

PI3K

PI3K

Cancer

Blood cancer

1260612-13-2

354.41

C19H22N4O3

>98% (HPLC)

DMSO : 125 mg/mL 352.71 mM

O=C1NC(CC(N2[C@@H](C)CC3=C2C=CC=C3)=O)=NC(N4CCOCC4)=C1

(S)-2-(2-(2-methylindolin-1-yl)-2-oxoethyl)-6-morpholinopyrimidin-4(1H)-one

(-20℃)

With Ice Pack

≥ 2 years