3L17

Discovery of (thienopyrimidin-2-yl)aminopyrimidines as Potent, Selective, and Orally Available Pan-PI3-Kinase and Dual Pan-PI3-Kinase/mTOR Inhibitors for the Treatment of Cancer

Summary for 3L17

• Entry DOI: 10.2210/pdb3l17/pdb
• Related: 3L13 3L16
• Descriptor: Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit gamma isoform, 4-methyl-5-(6-{[4-(methylsulfonyl)piperazin-1-yl]methyl}-4-morpholin-4-ylthieno[3,2-d]pyrimidin-2-yl)pyrimidin-2-amine (2 entities in total)
• Functional Keywords: kinase, atp-binding, nucleotide-binding, transferase, pi3k-gamma p110 gamma
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm : P48736
• Total number of polymer chains: 1
• Total formula weight: 111231.73

Authors

Murray, J.M.,Wiesmann, C. (deposition date: 2009-12-10, release date: 2010-02-16, Last modification date: 2023-09-06)

Primary citation

Sutherlin, D.P.,Sampath, D.,Berry, M.,Castanedo, G.,Chang, Z.,Chuckowree, I.,Dotson, J.,Folkes, A.,Friedman, L.,Goldsmith, R.,Heffron, T.,Lee, L.,Lesnick, J.,Lewis, C.,Mathieu, S.,Nonomiya, J.,Olivero, A.,Pang, J.,Prior, W.W.,Salphati, L.,Sideris, S.,Tian, Q.,Tsui, V.,Wan, N.C.,Wang, S.,Wiesmann, C.,Wong, S.,Zhu, B.Y.
Discovery of (Thienopyrimidin-2-yl)aminopyrimidines as Potent, Selective, and Orally Available Pan-PI3-Kinase and Dual Pan-PI3-Kinase/mTOR Inhibitors for the Treatment of Cancer.
J.Med.Chem., 53:1086-1097, 2010

PubMed Abstract: The PI3K/AKT/mTOR pathway has been shown to play an important role in cancer. Starting with compounds 1 and 2 (GDC-0941) as templates, (thienopyrimidin-2-yl)aminopyrimidines were discovered as potent inhibitors of PI3K or both PI3K and mTOR. Structural information derived from PI3K gamma-ligand cocrystal structures of 1 and 2 were used to design inhibitors that maintained potency for PI3K yet improved metabolic stability and oral bioavailability relative to 1. The addition of a single methyl group to the optimized 5 resulted in 21, which had significantly reduced potency for mTOR. The lead compounds 5 (GNE-493) and 21 (GNE-490) have good pharmacokinetic (PK) parameters, are highly selective, demonstrate knock down of pathway markers in vivo, and are efficacious in xenograft models where the PI3K pathway is deregulated. Both compounds were compared in a PI3K alpha mutated MCF7.1 xenograft model and were found to have equivalent efficacy when normalized for exposure.

PubMed: 20050669
DOI: 10.1021/jm901284w

Experimental method

X-RAY DIFFRACTION (3 Å)