6C1S

Phosphoinositide 3-Kinase gamma bound to an pyrrolopyridinone Inhibitor

Summary for 6C1S

• Entry DOI: 10.2210/pdb6c1s/pdb
• Descriptor: Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform, {4-[2-(5,6-dimethoxypyridin-3-yl)-5-oxo-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl]-1H-pyrazol-1-yl}acetonitrile, SULFATE ION, ... (4 entities in total)
• Functional Keywords: kinase, inhibitor, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 112029.38

Authors

Jacobs, M.D.,Griffin, J.P. (deposition date: 2018-01-05, release date: 2018-06-27, Last modification date: 2023-10-04)

Primary citation

Come, J.H.,Collier, P.N.,Henderson, J.A.,Pierce, A.C.,Davies, R.J.,Le Tiran, A.,O'Dowd, H.,Bandarage, U.K.,Cao, J.,Deininger, D.,Grey, R.,Krueger, E.B.,Lowe, D.B.,Liang, J.,Liao, Y.,Messersmith, D.,Nanthakumar, S.,Sizensky, E.,Wang, J.,Xu, J.,Chin, E.Y.,Damagnez, V.,Doran, J.D.,Dworakowski, W.,Griffith, J.P.,Jacobs, M.D.,Khare-Pandit, S.,Mahajan, S.,Moody, C.S.,Aronov, A.M.
Design and Synthesis of a Novel Series of Orally Bioavailable, CNS-Penetrant, Isoform Selective Phosphoinositide 3-Kinase gamma (PI3K gamma ) Inhibitors with Potential for the Treatment of Multiple Sclerosis (MS).
J. Med. Chem., 61:5245-5256, 2018

PubMed Abstract: The lipid kinase phosphoinositide 3-kinase γ (PI3Kγ) has attracted attention as a potential target to treat a variety of autoimmune disorders, including multiple sclerosis, due to its role in immune modulation and microglial activation. By minimizing the number of hydrogen bond donors while targeting a previously uncovered selectivity pocket adjacent to the ATP binding site of PI3Kγ, we discovered a series of azaisoindolinones as selective, brain penetrant inhibitors of PI3Kγ. This ultimately led to the discovery of 16, an orally bioavailable compound that showed efficacy in murine experimental autoimmune encephalomyelitis (EAE), a preclinical model of multiple sclerosis.

PubMed: 29847724
DOI: 10.1021/acs.jmedchem.8b00085

Experimental method

X-RAY DIFFRACTION (2.31 Å)