7LQ1

HUMAN PI3KDELTA IN COMPLEX WITH COMPOUND 28

Summary for 7LQ1

• Entry DOI: 10.2210/pdb7lq1/pdb
• Descriptor: Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform, Phosphatidylinositol 3-kinase regulatory subunit alpha, N-(5-(6-(2-((2S,6R)-2,6-dimethylmorpholino)pyridin-4-yl)-1-oxoisoindolin-4-yl)-2-methoxypyridin-3-yl)methanesulfonamide, ... (5 entities in total)
• Functional Keywords: pi3kdelta kinase, transferase, transferase-transferase inhibitor complex
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 2
• Total formula weight: 141071.64

Authors

Lesburg, C.A.,Augustin, M. (deposition date: 2021-02-12, release date: 2022-02-16, Last modification date: 2024-04-03)

Primary citation

Fradera, X.,Deng, Q.,Achab, A.,Garcia, Y.,Kattar, S.D.,McGowan, M.A.,Methot, J.L.,Wilson, K.,Zhou, H.,Shaffer, L.,Goldenblatt, P.,Tong, V.,Augustin, M.A.,Altman, M.D.,Lesburg, C.A.,Shah, S.,Katz, J.D.
Discovery of a new series of PI3K-delta inhibitors from Virtual Screening.
Bioorg.Med.Chem.Lett., 42:128046-128046, 2021

PubMed Abstract: PI3K-δ mediates key immune cell signaling pathways and is a target of interest for treatment of oncological and immunological disorders. Here we describe the discovery and optimization of a novel series of PI3K-δ selective inhibitors. We first identified hits containing an isoindolinone scaffold using a combined ligand- and receptor-based virtual screening workflow, and then improved potency and selectivity guided by structural data and modeling. Careful optimization of molecular properties led to compounds with improved permeability and pharmacokinetic profile, and high potency in a whole blood assay.

PubMed: 33865969
DOI: 10.1016/j.bmcl.2021.128046

Experimental method

X-RAY DIFFRACTION (2.96 Å)