4GB9

Potent and Highly Selective Benzimidazole Inhibitors of PI3K-delta

Summary for 4GB9

• Entry DOI: 10.2210/pdb4gb9/pdb
• Descriptor: Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform, 2-[1-({2-[2-(dimethylamino)-1H-benzimidazol-1-yl]-9-methyl-6-(morpholin-4-yl)-9H-purin-8-yl}methyl)piperidin-4-yl]propan-2-ol (3 entities in total)
• Functional Keywords: kinase p110 gamma-isoform, kinase, lipid kinase, 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: 111260.77

Authors

Murray, J.M. (deposition date: 2012-07-26, release date: 2012-08-22, Last modification date: 2023-09-13)

Primary citation

Murray, J.M.,Sweeney, Z.K.,Chan, B.K.,Balazs, M.,Bradley, E.,Castanedo, G.,Chabot, C.,Chantry, D.,Flagella, M.,Goldstein, D.M.,Kondru, R.,Lesnick, J.,Li, J.,Lucas, M.C.,Nonomiya, J.,Pang, J.,Price, S.,Salphati, L.,Safina, B.,Savy, P.P.,Seward, E.M.,Ultsch, M.,Sutherlin, D.P.
Potent and highly selective benzimidazole inhibitors of PI3-kinase delta.
J.Med.Chem., 55:7686-7695, 2012

PubMed Abstract: Inhibition of PI3Kδ is considered to be an attractive mechanism for the treatment of inflammatory diseases and leukocyte malignancies. Using a structure-based design approach, we have identified a series of potent and selective benzimidazole-based inhibitors of PI3Kδ. These inhibitors do not occupy the selectivity pocket between Trp760 and Met752 that is induced by other families of PI3Kδ inhibitors. Instead, the selectivity of the compounds for inhibition of PI3Kδ relative to other PI3K isoforms appears to be due primarily to the strong interactions these inhibitors are able to make with Trp760 in the PI3Kδ binding pocket. The pharmacokinetic properties and the ability of compound 5 to inhibit the function of B-cells in vivo are described.

PubMed: 22877085
DOI: 10.1021/jm300717c

Experimental method

X-RAY DIFFRACTION (2.438 Å)