3OAW

4-Methylpteridineones as Orally Active and Selective PI3K/mTOR Dual Inhibitors

Summary for 3OAW

• Entry DOI: 10.2210/pdb3oaw/pdb
• Related: 3ML8 3ML9
• Descriptor: Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit gamma isoform, 2-amino-4-methyl-8-(1-methylethyl)-6-(1H-pyrazol-4-yl)pteridin-7(8H)-one (3 entities in total)
• Functional Keywords: phosphoinositide kinase, transferase-transferase, inhibition, inhibitor complex., transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 111012.41

Authors

Knighton, D.R.,Greasley, S.E.,Rodgers, C.M.-L. (deposition date: 2010-08-05, release date: 2010-09-22, Last modification date: 2024-02-21)

Primary citation

Liu, K.K.,Bagrodia, S.,Bailey, S.,Cheng, H.,Chen, H.,Gao, L.,Greasley, S.,Hoffman, J.E.,Hu, Q.,Johnson, T.O.,Knighton, D.,Liu, Z.,Marx, M.A.,Nambu, M.D.,Ninkovic, S.,Pascual, B.,Rafidi, K.,Rodgers, C.M.,Smith, G.L.,Sun, S.,Wang, H.,Yang, A.,Yuan, J.,Zou, A.
4-methylpteridinones as orally active and selective PI3K/mTOR dual inhibitors.
Bioorg.Med.Chem.Lett., 20:6096-6099, 2010

PubMed Abstract: Pteridinones were designed based on a non-selective kinase template. Because of the uniqueness of the PI3K and mTOR binding pockets, a methyl group was introduced to C-4 position of the peteridinone core to give compounds with excellent selectivity for PI3K and mTOR. This series of compounds were further optimized to improve their potency against PI3Kα and mTOR. Finally, orally active compounds with improved solubility and robust in vivo efficacy in tumor growth inhibition were identified as well.

PubMed: 20817449
DOI: 10.1016/j.bmcl.2010.08.045

Experimental method

X-RAY DIFFRACTION (2.75 Å)