5EDS

Crystal structure of human PI3K-gamma in complex with benzimidazole inhibitor 5

Summary for 5EDS

• Entry DOI: 10.2210/pdb5eds/pdb
• Descriptor: Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform, SULFATE ION, 4-azanyl-6-[[(1~{S})-1-[6-fluoranyl-1-(3-methylsulfonylphenyl)benzimidazol-2-yl]ethyl]amino]pyrimidine-5-carbonitrile, ... (4 entities in total)
• Functional Keywords: inhibitor, phosphotransferase, p110, 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: 110506.67

Authors

Whittington, D.A.,Tang, J.,Yakowec, P. (deposition date: 2015-10-21, release date: 2015-12-30, Last modification date: 2023-09-27)

Primary citation

Shin, Y.,Suchomel, J.,Cardozo, M.,Duquette, J.,He, X.,Henne, K.,Hu, Y.L.,Kelly, R.C.,McCarter, J.,McGee, L.R.,Medina, J.C.,Metz, D.,San Miguel, T.,Mohn, D.,Tran, T.,Vissinga, C.,Wong, S.,Wannberg, S.,Whittington, D.A.,Whoriskey, J.,Yu, G.,Zalameda, L.,Zhang, X.,Cushing, T.D.
Discovery, Optimization, and in Vivo Evaluation of Benzimidazole Derivatives AM-8508 and AM-9635 as Potent and Selective PI3K delta Inhibitors.
J.Med.Chem., 59:431-447, 2016

PubMed Abstract: Lead optimization efforts resulted in the discovery of two potent, selective, and orally bioavailable PI3Kδ inhibitors, 1 (AM-8508) and 2 (AM-9635), with good pharmacokinetic properties. The compounds inhibit B cell receptor (BCR)-mediated AKT phosphorylation (pAKT) in PI3Kδ-dependent in vitro cell based assays. These compounds which share a benzimidazole bicycle are effective when administered in vivo at unbound concentrations consistent with their in vitro cell potency as a consequence of improved unbound drug concentration with lower unbound clearance. Furthermore, the compounds demonstrated efficacy in a Keyhole Limpet Hemocyanin (KLH) study in rats, where the blockade of PI3Kδ activity by inhibitors 1 and 2 led to effective inhibition of antigen-specific IgG and IgM formation after immunization with KLH.

PubMed: 26652588
DOI: 10.1021/acs.jmedchem.5b01651

Experimental method

X-RAY DIFFRACTION (2.8 Å)