- Discovery and biological activity of a novel class i PI3K inhibitor, CH5132799
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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 (IC50 = 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.
- Ohwada, Jun,Ebiike, Hirosato,Kawada, Hatsuo,Tsukazaki, Masao,Nakamura, Mitsuaki,Miyazaki, Takuya,Morikami, Kenji,Yoshinari, Kiyoshi,Yoshida, Miyuki,Kondoh, Osamu,Kuramoto, Shino,Ogawa, Kotaro,Aoki, Yuko,Shimma, Nobuo
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p. 1767 - 1772
(2011/05/05)
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- PYRROLOPYRIMIDIN DERIVATIVE FOR USE AS PI3K INHIBITOR, AND USE THEREOF
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A preventive or therapeutic agent of a proliferative disease such as cancer, having superior PI3K inhibitory effects, superior cell proliferation inhibitory action as well as superior stability in a body and water solubility, is provided. A compound represented by formula (I): [wherein, Q represents a linking group represented by -X-Y-; X represents a single bond -CO-, -CONH-, -CON(C1-4 alkyl)-, -CS-, -CSNH-, -CSN(C1-4 alkyl)-, or -SO2-; Y represents a single bond, arylene or heteroarylene; provided that X and Y are not simultaneously single bonds; and R1 represents -C0-6 alkylene-(A)m-C1-6 alkyl, or C0-6 alkylene-(A)m-C0-6 alkylene-(heterocycle)] or a pharmaceutically acceptable salt thereof.
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Page/Page column 38-39
(2010/11/03)
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