7POR

PI3 kinase delta in complex with N-[2-(2-fluoro-4-{[4-(propan-2-yl)piperazin-1-yl]methyl}phenyl)pyridin-4-yl]-2-methoxy-5-(morpholin-4-yl)pyridine-3-sulfonamide

Summary for 7POR

• Entry DOI: 10.2210/pdb7por/pdb
• Descriptor: Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform, ~{N}-[2-[2-fluoranyl-4-[(4-propan-2-ylpiperazin-1-yl)methyl]phenyl]pyridin-4-yl]-2-methoxy-5-morpholin-4-yl-pyridine-3-sulfonamide (3 entities in total)
• Functional Keywords: pi3 kinase delta, signaling protein
• Biological source: Mus musculus (Mouse)
• Total number of polymer chains: 1
• Total formula weight: 108408.37

Authors

Rowland, P.,Convery, M. (deposition date: 2021-09-09, release date: 2021-09-29, Last modification date: 2024-06-19)

Primary citation

Down, K.,Amour, A.,Anderson, N.A.,Barton, N.,Campos, S.,Cannons, E.P.,Clissold, C.,Convery, M.A.,Coward, J.J.,Doyle, K.,Duempelfeld, B.,Edwards, C.D.,Goldsmith, M.D.,Krause, J.,Mallett, D.N.,McGonagle, G.A.,Patel, V.K.,Rowedder, J.,Rowland, P.,Sharpe, A.,Sriskantharajah, S.,Thomas, D.A.,Thomson, D.W.,Uddin, S.,Hamblin, J.N.,Hessel, E.M.
Discovery of GSK251: A Highly Potent, Highly Selective, Orally Bioavailable Inhibitor of PI3K delta with a Novel Binding Mode.
J.Med.Chem., 64:13780-13792, 2021

PubMed Abstract: Optimization of a previously reported lead series of PI3Kδ inhibitors with a novel binding mode led to the identification of a clinical candidate compound (GSK251). Removal of an embedded Ames-positive heteroaromatic amine by reversing a sulfonamide followed by locating an interaction with Trp760 led to a highly selective compound . Further optimization to avoid glutathione trapping, to enhance potency and selectivity, and to optimize an oral pharmacokinetic profile led to the discovery of compound (GSK215) that had a low predicted daily dose (45 mg, b.i.d) and a rat toxicity profile suitable for further development.

PubMed: 34510892
DOI: 10.1021/acs.jmedchem.1c01102

Experimental method

X-RAY DIFFRACTION (2.26 Å)