7JIU

HUMAN PI3KDELTA IN COMPLEX WITH COMPOUND 2F

7JIU の概要

• エントリーDOI: 10.2210/pdb7jiu/pdb
• 分子名称: Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform, (3S)-3-benzyl-5-[9-ethyl-8-(2-methylpyrimidin-5-yl)-9H-purin-6-yl]-3-methyl-1,3-dihydro-2H-indol-2-one (3 entities in total)
• 機能のキーワード: pi3kalpha kinase, transferase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 110559.74

構造登録者

Lesburg, C.A.,Augustin, M. (登録日: 2020-07-23, 公開日: 2021-06-30, 最終更新日: 2024-04-03)

主引用文献

Methot, J.L.,Achab, A.,Christopher, M.,Zhou, H.,McGowan, M.A.,Trotter, B.W.,Fradera, X.,Lesburg, C.A.,Goldenblatt, P.,Hill, A.,Chen, D.,Otte, K.M.,Augustin, M.,Shah, S.,Katz, J.D.
Optimization of Versatile Oxindoles as Selective PI3K delta Inhibitors.
Acs Med.Chem.Lett., 11:2461-2469, 2020

PubMed Abstract: The 3,3-disubstituted oxindole moiety is a versatile and rigid three-dimensionally shaped scaffold. When engineered with a purine hinge-binding core, exceptionally selective PI3Kδ kinase inhibitors were discovered by exploiting small differences in isoform selectivity pockets. Crystal structures of early lead bound to PI3Kδ and PI3Kα helped rationalize the high selectivity observed with . By attenuating the lypophilicity and metabolic liabilities of an oxindole moiety, we improved the preclinical species PK and solubility and reduced adenosine uptake activity. The excellent potency and kinome selectivity of 7-azaoxindole and spirooxindole , together with a low plasma clearance and good half-life in rat and dog, supported a low once-daily predicted human dose.

PubMed: 33335668
DOI: 10.1021/acsmedchemlett.0c00441

実験手法

X-RAY DIFFRACTION (2.12 Å)