7JIU

HUMAN PI3KDELTA IN COMPLEX WITH COMPOUND 2F

Summary for 7JIU

• Entry DOI: 10.2210/pdb7jiu/pdb
• Descriptor: 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)
• Functional Keywords: pi3kalpha kinase, transferase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 110559.74

Authors

Lesburg, C.A.,Augustin, M. (deposition date: 2020-07-23, release date: 2021-06-30, Last modification date: 2024-04-03)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.12 Å)