3TL5

Discovery of GDC-0980: a Potent, Selective, and Orally Available Class I Phosphatidylinositol 3-Kinase (PI3K)/Mammalian Target of Rapamycin (mTOR) Kinase Inhibitor for the Treatment of Cancer

3TL5 の概要

• エントリーDOI: 10.2210/pdb3tl5/pdb
• 分子名称: Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit gamma isoform, (2S)-1-(4-{[2-(2-aminopyrimidin-5-yl)-7-methyl-4-(morpholin-4-yl)thieno[3,2-d]pyrimidin-6-yl]methyl}piperazin-1-yl)-2-hydroxypropan-1-one (3 entities in total)
• 機能のキーワード: transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Cytoplasm: P48736
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 111225.70

構造登録者

Murray, J.M.,Wiesmann, C. (登録日: 2011-08-29, 公開日: 2011-11-02, 最終更新日: 2023-09-13)

主引用文献

Sutherlin, D.P.,Bao, L.,Berry, M.,Castanedo, G.,Chuckowree, I.,Dotson, J.,Folks, A.,Friedman, L.,Goldsmith, R.,Gunzner, J.,Heffron, T.,Lesnick, J.,Lewis, C.,Mathieu, S.,Murray, J.,Nonomiya, J.,Pang, J.,Pegg, N.,Prior, W.W.,Rouge, L.,Salphati, L.,Sampath, D.,Tian, Q.,Tsui, V.,Wan, N.C.,Wang, S.,Wei, B.,Wiesmann, C.,Wu, P.,Zhu, B.Y.,Olivero, A.
Discovery of a Potent, Selective, and Orally Available Class I Phosphatidylinositol 3-Kinase (PI3K)/Mammalian Target of Rapamycin (mTOR) Kinase Inhibitor (GDC-0980) for the Treatment of Cancer.
J.Med.Chem., 54:7579-7587, 2011

PubMed Abstract: The discovery of 2 (GDC-0980), a class I PI3K and mTOR kinase inhibitor for oncology indications, is described. mTOR inhibition was added to the class I PI3K inhibitor 1 (GDC-0941) scaffold primarily through the substitution of the indazole in 1 for a 2-aminopyrimidine. This substitution also increased the microsomal stability and the free fraction of compounds as evidenced through a pairwise comparison of molecules that were otherwise identical. Highlighted in detail are analogues of an advanced compound 4 that were designed to improve solubility, resulting in 2. This compound, is potent across PI3K class I isoforms with IC(50)s of 5, 27, 7, and 14 nM for PI3Kα, β, δ, and γ, respectively, inhibits mTOR with a K(i) of 17 nM yet is highly selective versus a large panel of kinases including others in the PIKK family. On the basis of the cell potency, low clearance in mouse, and high free fraction, 2 demonstrated significant efficacy in mouse xenografts when dosed as low as 1 mg/kg orally and is currently in phase I clinical trials for cancer.

PubMed: 21981714
DOI: 10.1021/jm2009327

実験手法

X-RAY DIFFRACTION (2.788 Å)