7KKE

Phosphoinositide 3-Kinase gamma bound to a thiazole inhibitor

Summary for 7KKE

• Entry DOI: 10.2210/pdb7kke/pdb
• Descriptor: Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform, N-[2-(3,3-dimethylbutoxy)ethyl]-N'-{4-methyl-5-[(pyridin-4-yl)ethynyl]-1,3-thiazol-2-yl}urea (3 entities in total)
• Functional Keywords: kinase, inhibitor, transferase-inhibitor complex, transferase/inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 111655.27

Authors

Jacobs, M.D.,Griffith, J.P. (deposition date: 2020-10-27, release date: 2021-03-24, Last modification date: 2023-10-18)

Primary citation

Bandarage, U.K.,Aronov, A.M.,Cao, J.,Come, J.H.,Cottrell, K.M.,Davies, R.J.,Giroux, S.,Jacobs, M.,Mahajan, S.,Messersmith, D.,Moody, C.S.,Swett, R.,Xu, J.
Discovery of a Novel Series of Potent and Selective Alkynylthiazole-Derived PI3K gamma Inhibitors.
Acs Med.Chem.Lett., 12:129-135, 2021

PubMed Abstract: Phosphoinositide 3-kinases (PI3Ks) are a family of enzymes that control a wide variety of cellular functions such as cell growth, proliferation, differentiation, motility, survival, and intracellular trafficking. PI3Kγ plays a critical role in mediating leukocyte chemotaxis as well as mast cell degranulation, making it a potentially interesting target for autoimmune and inflammatory diseases. We previously disclosed a novel series of PI3Kγ inhibitors derived from a benzothiazole core. The truncation of the benzothiazole core led to the discovery of a structurally diverse alkynyl thiazole series which displayed high PI3Kγ potency and subtype selectivity. Further medicinal chemistry optimization of the alkynyl thiazole series led to identification of compounds such as and , highly potent, subtype selective, and CNS penetrant PI3Kγ inhibitors. Compound showed robust inhibition of PI3Kγ mediated neutrophil migration .

PubMed: 33488974
DOI: 10.1021/acsmedchemlett.0c00573

Experimental method

X-RAY DIFFRACTION (2.81 Å)