Discovery and biological activity of a novel class I PI3K inhibitor, CH5132799

  • Bioorg Med Chem Lett. 2011 Mar 15;21(6):1767-72. doi: 10.1016/j.bmcl.2011.01.065.
Jun Ohwada  1 ,  Hirosato Ebiike ,  Hatsuo Kawada ,  Masao Tsukazaki ,  Mitsuaki Nakamura ,  Takuya Miyazaki ,  Kenji Morikami ,  Kiyoshi Yoshinari ,  Miyuki Yoshida ,  Osamu Kondoh ,  Shino Kuramoto ,  Kotaro Ogawa ,  Yuko Aoki ,  Nobuo Shimma
Affiliations
  • 1. Research Division, Chugai Pharmaceutical Co., Ltd , Kamakura, Kanagawa, Japan. [email protected]
PMID: 21316229 DOI: 10.1016/j.bmcl.2011.01.065
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.

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