6TNS

PI3K delta in complex with 2methoxyN[2methoxy5(7{[(2R)4(oxetan3 yl)morpholin2yl]methoxy}1,3dihydro2 benzofuran5yl)pyridin3yl]ethane1 sulfonamide

Summary for 6TNS

• Entry DOI: 10.2210/pdb6tns/pdb
• Descriptor: Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform, 2-methoxy-~{N}-[2-methoxy-5-[7-[[(2~{R})-4-(oxetan-3-yl)morpholin-2-yl]methoxy]-1,3-dihydro-2-benzofuran-5-yl]pyridin-3-yl]ethanesulfonamide (3 entities in total)
• Functional Keywords: pi3 kinase structure based design, transferase
• Biological source: Mus musculus (House mouse)
• Total number of polymer chains: 1
• Total formula weight: 108359.27

Authors

Convery, M.A.,Rowland, P.,Henley, Z.A.,Barton, N.,Down, K. (deposition date: 2019-12-10, release date: 2020-01-01, Last modification date: 2024-06-19)

Primary citation

Henley, Z.A.,Amour, A.,Barton, N.,Bantscheff, M.,Bergamini, G.,Bertrand, S.M.,Convery, M.,Down, K.,Dumpelfeld, B.,Edwards, C.D.,Grandi, P.,Gore, P.M.,Keeling, S.,Livia, S.,Mallett, D.,Maxwell, A.,Price, M.,Rau, C.,Reinhard, F.B.M.,Rowedder, J.,Rowland, P.,Taylor, J.A.,Thomas, D.A.,Hessel, E.M.,Hamblin, J.N.
Optimization of Orally Bioavailable PI3K delta Inhibitors and Identification of Vps34 as a Key Selectivity Target.
J.Med.Chem., 63:638-655, 2020

PubMed Abstract: Optimization of a lead series of PI3Kδ inhibitors based on a dihydroisobenzofuran core led to the identification of potent, orally bioavailable compound . Selectivity profiling of compound showed similar potency for class III PI3K, Vps34, and PI3Kδ, and compound was not well-tolerated in a 7-day rat toxicity study. Structure-based design led to an improvement in selectivity for PI3Kδ over Vps34 and, a focus on oral phramacokinetics properties resulted in the discovery of compound , which showed improved toxicological outcomes at similar exposure levels to compound .

PubMed: 31855425
DOI: 10.1021/acs.jmedchem.9b01585

Experimental method

X-RAY DIFFRACTION (2.4 Å)