The phosphatidylinositol 3-kinase (PI3K) signaling pathway regulates a number of crucial cellular processes, including growth, survival, angiogenesis, migration and metabolism. The PI3K family consists of four isoforms: Class I, Class II, Class III, and Class IV. Class I PI3K enzymes consist of four distinct catalytic isoforms, PI3Kα, PI3Kβ, PI3Kδ and PI3Kγ. Furthermore, PI3K signaling is frequently dysregulated in cancer resulting in persistent pathway activation. Genetic or epigenetic inactivation of the negative regulator of PI3K activity, the tumor suppressor PTEN, in a number of cancers.
SN32976 is a potent and selective class I PI3K and mTOR inhibitor.
This compound potently inhibits PI3Kα, PI3Kβ, PI3Kγ, PI3Kδ and mTOR, displaying preferential activity for PI3Kα. Moreover, SN32976 has an IC50 of 15.1 nM against PI3Kα and shows 7.3-fold, 8.9-fold, 13-fold and 30-fold selectivity against PI3Kγ, PI3Kδ, mTOR and PI3Kβ, respectively. In addition, SN32976 shows high selectivity among other 442 kinases and exhibits strong anticancer effects. In vitro, SN32976 inhibits both Thr308 and Ser473 pAKT expression in U-87 MG cells at concentrations as low as 10 nM. Meanwhile, SN32976 potently inhibits cell proliferation in a panel of cell lines with dysregulated PI3K signaling.
Importantly, in vivo, SN32976 is highly soluble at low pH, is moderately bound to plasma proteins and has reasonable stability in liver microsomes. Aslo, it does not inhibit any of the major CYP isoforms. In NIH-III mice with PIK3CA-mutant NCI-H460 tumors, SN32976 (single dose; 37.5-100 mg/kg) substantially inhibits the expression of pAKT (both Ser473 and Thr308) for 24 h. Besides, in mice with U-87 MG, NCI-H460 and HCT116 tumors, SN32976 potently inhibis tumor growth.
To sum up, SN32976 is a selective class I PI3K and mTOR inhibitor with potent anticancer activities.
References:
[1] Gordon W Rewcastle, et al. Oncotarget. 2017 Jul 18;8(29):47725-47740.