1007207-67-1

CH5132799 is a selective class I phosphoinositide 3-kinase (PI3K) inhibitor that targets human cancers harboring oncogenic PIK3CA mutations. CH5132799 also showed potent antiproliferative and antitumor activity.

ch5132799 is an inhibitor of class i phosphatidylinositol 3-kinase (pi3k) with ic50 value of 14nm against pi3kα [1].ch5132799 shows inhibitory effect on class i pi3k with ic50 values of 0.014μm, 0.12μm, 0.5μm and 0.036μm against pi3kα, pi3kβ, pi3kδ and pi3kγ, respectively. pi3kα is especially sensitive to ch5132799. ch5132799 is a selective inhibitor. it shows less effect on class ii pi3ks, class iii pi3k and mtor. for other 26 protein kinases, ch5132799 nearly has no inhibition with ic50 value of > 10μm. ch5132799 is found to have potent antitumor activity. it exerts ic50 values of 0.2μm, 0.032μm, 0.056μm and 0.12μm in hct116, kpl-4, t-47d and sk-ov-3 cell lines, respectively. moreover, ch5132799 is oral available in animal models. treatment of ch5132799 shows strong tumor regression at dose of 12.5 mg/kg in mice bearing human breast cancer xenografts [1].

GENERAL STEPS: To DMF (550 mL) under nitrogen protection were added 4-chloro-7-methanesulfonyl-2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine (57.9 g, 181.6 mmol), 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine ( 48.2 g, 218.0 mmol), potassium phosphate (42.4 g, 199.8 mmol) and water (30 mL) and degassed. Subsequently, dichlorobis(triphenylphosphine)palladium(II) (1.3 g, 1.8 mmol) was added, degassed again, and then the reaction was stirred at 60 °C for 2 hours. After completion of the reaction, the reaction mixture was cooled in an ice bath, water (750 mL) was added and stirring was continued for 2 hours. The precipitate was collected by filtration and washed sequentially with water (240 mL) and acetone (240 mL) to give the crude product (75.6 g). The crude product (62.0 g) was suspended in water (1500 mL) and stirred at 50 °C for 1 hour. The suspension was filtered and washed sequentially with water (400 mL) and acetone (400 mL) to afford 5-(7-methylsulfonyl-2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrimidin-2-amine as an off-white solid (53.7 g, 96% yield).

PI3Kα

PI3Kα: 14 nM (IC₅₀); PI3Kα-H1047R: 5.6 nM (IC₅₀); PI3Kα-E545K: 6.7 nM (IC₅₀); PI3Kα-E542K: 6.7 nM (IC₅₀); PI3Kγ: 36 nM (IC₅₀); PI3Kβ: 120 nM (IC₅₀); PI3Kδ: 500 nM (IC₅₀); PI3KC2β: 5.3 μM (IC₅₀); mTOR: 1.6 μM (IC₅₀)

Store at -20°C

[1] ohwada j, ebiike h, kawada h, et al. discovery and biological activity of a novel class i pi3k inhibitor, ch5132799. bioorganic & medicinal chemistry letters, 2011, 21(6): 1767-1772.