6OCU

HUMAN PI3KDELTA IN COMPLEX WITH COMPOUND 29

Summary for 6OCU

• Entry DOI: 10.2210/pdb6ocu/pdb
• Descriptor: Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform, Phosphatidylinositol 3-kinase regulatory subunit alpha, 5-{(3R)-3-methyl-4-[(1R,2R)-2-methylcyclopropane-1-carbonyl]piperazin-1-yl}-3-(1-methyl-1H-pyrazol-4-yl)pyrazine-2-carbonitrile (3 entities in total)
• Functional Keywords: pi3kdelta kinase, transferase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 2
• Total formula weight: 142966.46

Authors

Lesburg, C.A.,Augustin, M.A. (deposition date: 2019-03-25, release date: 2019-12-11, Last modification date: 2024-03-13)

Primary citation

Zhou, H.,McGowan, M.A.,Lipford, K.,Christopher, M.,Fradera, X.,Witter, D.,Lesburg, C.A.,Li, C.,Methot, J.L.,Lampe, J.,Achab, A.,Shaffer, L.,Goldenblatt, P.,Shah, S.,Bass, A.,Schroeder, G.,Chen, D.,Zeng, H.,Augustin, M.A.,Katz, J.D.
Discovery and optimization of heteroaryl piperazines as potent and selective PI3K delta inhibitors.
Bioorg.Med.Chem.Lett., 30:126715-126715, 2020

PubMed Abstract: A high-throughput screening (HTS) campaign identified a class of heteroaryl piperazines with excellent baseline affinity and selectivity for phosphoinositide 3-kinase δ (PI3Kδ) over closely related isoforms. Rapid evaluation and optimization of structure-activity relationships (SAR) for this class, leveraging the modular nature of this scaffold, facilitated development of this hit class into a series of potent and selective inhibitors of PI3Kδ. This effort culminated in the identification of 29, which displayed excellent potency in enzyme and cell-based assays, as well as favorable pharmacokinetic and off-target profiles.

PubMed: 31757666
DOI: 10.1016/j.bmcl.2019.126715

Experimental method

X-RAY DIFFRACTION (2.77 Å)