4RIO

Crystal structure of JAK3 kinase domain in complex with a pyrrolopyridazine carboxamide inhibitor

Summary for 4RIO

• Entry DOI: 10.2210/pdb4rio/pdb
• Descriptor: Tyrosine-protein kinase JAK3, 4-{[(1R,2S)-2-fluoro-2-methylcyclopentyl]amino}pyrrolo[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: 33530.33

Authors

Sack, J.S. (deposition date: 2014-10-07, release date: 2014-12-24, Last modification date: 2024-02-28)

Primary citation

Duan, J.J.,Lu, Z.,Jiang, B.,Yang, B.V.,Doweyko, L.M.,Nirschl, D.S.,Haque, L.E.,Lin, S.,Brown, G.,Hynes, J.,Tokarski, J.S.,Sack, J.S.,Khan, J.,Lippy, J.S.,Zhang, R.F.,Pitt, S.,Shen, G.,Pitts, W.J.,Carter, P.H.,Barrish, J.C.,Nadler, S.G.,Salter-Cid, L.M.,McKinnon, M.,Fura, A.,Schieven, G.L.,Wrobleski, S.T.
Discovery of pyrrolo[1,2-b]pyridazine-3-carboxamides as Janus kinase (JAK) inhibitors.
Bioorg.Med.Chem.Lett., 24:5721-5726, 2014

PubMed Abstract: A new class of Janus kinase (JAK) inhibitors was discovered using a rationally designed pyrrolo[1,2-b]pyridazine-3-carboxamide scaffold. Preliminary studies identified (R)-(2,2-dimethylcyclopentyl)amine as a preferred C4 substituent on the pyrrolopyridazine core (3b). Incorporation of amino group to 3-position of the cyclopentane ring resulted in a series of JAK3 inhibitors (4g-4j) that potently inhibited IFNγ production in an IL2-induced whole blood assay and displayed high functional selectivity for JAK3-JAK1 pathway relative to JAK2. Further modifications led to the discovery of an orally bioavailable (2-fluoro-2-methylcyclopentyl)amino analogue 5g which is a nanomolar inhibitor of both JAK3 and TYK2, functionally selective for the JAK3-JAK1 pathway versus JAK2, and active in a human whole blood assay.

PubMed: 25453808
DOI: 10.1016/j.bmcl.2014.10.061

Experimental method

X-RAY DIFFRACTION (2.69 Å)