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

Summary for 3TL5

• Entry DOI: 10.2210/pdb3tl5/pdb
• Descriptor: 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)
• Functional Keywords: transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm: P48736
• Total number of polymer chains: 1
• Total formula weight: 111225.70

Authors

Murray, J.M.,Wiesmann, C. (deposition date: 2011-08-29, release date: 2011-11-02, Last modification date: 2023-09-13)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.788 Å)