6NY4

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

Summary for 6NY4

• Entry DOI: 10.2210/pdb6ny4/pdb
• Descriptor: Tyrosine-protein kinase JAK3, 4-{[(2R,3R)-1,3-dihydroxybutan-2-yl]amino}-6-phenylpyrrolo[1,2-b]pyridazine-3-carboxamide (3 entities in total)
• Functional Keywords: transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 33594.39

Authors

Sack, J.S. (deposition date: 2019-02-11, release date: 2019-05-22, Last modification date: 2024-03-13)

Primary citation

Spergel, S.H.,Mertzman, M.E.,Kempson, J.,Guo, J.,Stachura, S.,Haque, L.,Lippy, J.S.,Zhang, R.F.,Galella, M.,Pitt, S.,Shen, G.,Fura, A.,Gillooly, K.,McIntyre, K.W.,Tang, V.,Tokarski, J.,Sack, J.S.,Khan, J.,Carter, P.H.,Barrish, J.C.,Nadler, S.G.,Salter-Cid, L.M.,Schieven, G.L.,Wrobleski, S.T.,Pitts, W.J.
Discovery of a JAK1/3 Inhibitor and Use of a Prodrug To Demonstrate Efficacy in a Model of Rheumatoid Arthritis.
Acs Med.Chem.Lett., 10:306-311, 2019

PubMed Abstract: The four members of the Janus family of nonreceptor tyrosine kinases play a significant role in immune function. The JAK family kinase inhibitor, tofacitinib , has been approved in the United States for use in rheumatoid arthritis (RA) patients. A number of JAK inhibitors with a variety of JAK family selectivity profiles are currently in clinical trials. Our goal was to identify inhibitors that were functionally selective for JAK1 and JAK3. Compound was prepared with the desired functional selectivity profile, but it suffered from poor absorption related to physical properties. Use of the phosphate prodrug enabled progression to a murine collagen induced arthritis (CIA) model. The demonstration of a robust efficacy in the CIA model suggests that use of phosphate prodrugs may resolve issues with progressing this chemotype for the treatment of autoimmune diseases such as RA.

PubMed: 30891131
DOI: 10.1021/acsmedchemlett.8b00508

Experimental method

X-RAY DIFFRACTION (2.33 Å)