Description
GSK2126458 is a potent inhibitor of phosphoinositide 3-kinase isoforms (K
is = 19, 130, 24, and 60 pM for p110α, β, δ, and γ, respectively). It also inhibits mTOR in both mTORC1 and mTORC2 (K
is = 180 and 300 nM, respectively), as well as several common mutant forms of p110α. GSK2126458 is orally bioavailable, displays favorable pharmacokinetics, and shows efficacy in tumor growth models. GSK2126458 positively combines with inhibitors of discoidin domain receptor 1 (DDR1) inhibitor DDR1-IN-1 to suppress the growth of SNU-1040 colorectal cancer cells.
Uses
A highly potent inhibitor of PI3K and the mammalian target of Rapamycin.
Definition
ChEBI: Omipalisib is a member of the class of quinolines that is quinoline which is substituted by pyridazin-4-yl and 5-[(2,4-difluorobenzene-1-sulfonyl)amino]-6-methoxypyridin-3-yl groups at positions 4 and 6, respectively. It is a highly potent inhibitor of PI3K and mTOR developed by GlaxoSmithKline and was previously in human phase 1 clinical trials for the treatment of idiopathic pulmonary fibrosis and solid tumors. It has a role as an autophagy inducer, an EC 2.7.1.137 (phosphatidylinositol 3-kinase) inhibitor, a mTOR inhibitor, an antineoplastic agent, a radiosensitizing agent and an anticoronaviral agent. It is a member of quinolines, a difluorobenzene, a sulfonamide, an aromatic ether, a member of pyridines and a member of pyridazines.
Synthesis
b) Synthesis of 2,4-difluoro-N-{2-methoxy-5-[4-(pyridazin-4-yl)quinolin-6-yl]pyridin-3-yl}benzenesulfonamide: 6-bromo-4-(pyridazin-4-yl)quinoline (4.8 g, 16.78 mmol), bis(pinacolato)diboron (4.69 g, 18.45 mmol), PdCl2(dppf)- CH2Cl2 (530 mg, 0.649 mmol) and anhydrous potassium acetate (3.29 g, 33.6 mmol) were dissolved in 1,4-dioxane (120 ml) and the reaction was heated at 100 °C for 3 hours. After monitoring the reaction by LCMS and confirming the complete disappearance of the starting bromide, N-[5-bromo-2-methoxypyridin-3-yl]-2,4-difluorobenzenesulfonamide (6.68 g, 17.61 mmol) and another portion of PdCl2(dppf)-CH2Cl2 (550 mg, 0.673 mmol) were added and the reaction was continued to be heated for 16 hr at 110 °C. After completion of the reaction, it was cooled to room temperature, filtered and concentrated. The residue was purified by column chromatography (Analogix system; eluent: 5% methanol/5% dichloromethane/90% ethyl acetate) to give 6.5 g (76% yield) of the target product. Mass spectrum (electrospray ionization, positive ion mode) m/e 505.9 [M+H]+.
References
[1] Patent: US2013/317037, 2013, A1. Location in patent: Paragraph 0104
