5VO6

CRYSTAL STRUCTURE OF JAK3 KINASE DOMAIN IN COMPLEX WITH A PYRROLOPYRIDAZINE INHIBITOR

Summary for 5VO6

• Entry DOI: 10.2210/pdb5vo6/pdb
• Descriptor: Tyrosine-protein kinase JAK3, 4-{[(1R,3S)-3-amino-2,2,3-trimethylcyclopentyl]amino}-6-phenylpyrrolo[1,2-b]pyridazine-3-carboxamide (3 entities in total)
• Functional Keywords: transferase, transferase-inhibitor complex, transferase/inhibitor
• Biological source: Homo sapiens (Human)
• Cellular location: Endomembrane system ; Peripheral membrane protein : P52333
• Total number of polymer chains: 1
• Total formula weight: 33631.50

Authors

Sack, J.S. (deposition date: 2017-05-02, release date: 2017-05-31, Last modification date: 2024-03-13)

Primary citation

Hynes, J.,Wu, H.,Kempson, J.,Duan, J.J.,Lu, Z.,Jiang, B.,Stachura, S.,Tokarski, J.S.,Sack, J.S.,Khan, J.A.,Lippy, J.S.,Zhang, R.F.,Pitt, S.,Shen, G.,Gillooly, K.,McIntyre, K.,Carter, P.H.,Barrish, J.C.,Nadler, S.G.,Salter-Cid, L.M.,Fura, A.,Schieven, G.L.,Pitts, W.J.,Wrobleski, S.T.
Discovery of potent and efficacious pyrrolopyridazines as dual JAK1/3 inhibitors.
Bioorg. Med. Chem. Lett., 27:3101-3106, 2017

PubMed Abstract: A series of potent dual JAK1/3 inhibitors have been developed from a moderately selective JAK3 inhibitor. Substitution at the C6 position of the pyrrolopyridazine core with aryl groups provided exceptional biochemical potency against JAK1 and JAK3 while maintaining good selectivity against JAK2 and Tyk2. Translation to in vivo efficacy was observed in a murine model of chronic inflammation. X-ray co-crystal structure determination confirmed the presumed inhibitor binding orientation in JAK3. Efforts to reduce hERG channel inhibition will be described.

PubMed: 28539220
DOI: 10.1016/j.bmcl.2017.05.043

Experimental method

X-RAY DIFFRACTION (2.65 Å)