title: Discovery and biological activity of a novel class I PI3K inhibitor, CH5132799.
abstract: Phosphatidylinositol 3-kinase (PI3K) is a lipid kinase and a promising therapeutic target for cancer. Using structure-based drug design (SBDD), we have identified novel PI3K inhibitors with a dihydropyrrolopyrimidine skeleton. Metabolic stability of the first lead series was drastically improved by replacing phenol with aminopyrimidine moiety. CH5132799, a novel class I PI3K inhibitor, exhibited a strong inhibitory activity especially against PI3Kα (IC(50)=0.014 μM). In human tumor cell lines with PI3K pathway activation, CH5132799 showed potent antiproliferative activity. CH5132799 is orally available and showed significant antitumor activity in PI3K pathway-activated human cancer xenograft models in mice.
authors.affiliation: Research Division, Chugai Pharmaceutical Co., Ltd , Kamakura, Kanagawa, Japan. ohwadajn@chugai-pharm.co.jp
authors.forename: Jun
authors.initials: J
authors.lastname: Ohwada
authors.forename: Hirosato
authors.initials: H
authors.lastname: Ebiike
authors.forename: Hatsuo
authors.initials: H
authors.lastname: Kawada
authors.forename: Masao
authors.initials: M
authors.lastname: Tsukazaki
authors.forename: Mitsuaki
authors.initials: M
authors.lastname: Nakamura
authors.forename: Takuya
authors.initials: T
authors.lastname: Miyazaki
authors.forename: Kenji
authors.initials: K
authors.lastname: Morikami
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Yoshinari
authors.forename: Miyuki
authors.initials: M
authors.lastname: Yoshida
authors.forename: Osamu
authors.initials: O
authors.lastname: Kondoh
authors.forename: Shino
authors.initials: S
authors.lastname: Kuramoto
authors.forename: Kotaro
authors.initials: K
authors.lastname: Ogawa
authors.forename: Yuko
authors.initials: Y
authors.lastname: Aoki
authors.forename: Nobuo
authors.initials: N
authors.lastname: Shimma
mesh_terms: D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D008958:Models, Molecular; D019869:Phosphatidylinositol 3-Kinases / Q000737:chemistry; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011743:Pyrimidines / Q000494:pharmacology*; D013449:Sulfonamides / Q000494:pharmacology*
chemical_list: D004791:Enzyme Inhibitors; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011743:Pyrimidines; D013449:Sulfonamides; C559137:CH 5132799