6AAK

Crystal structure of JAK3 in complex with peficitinib

Summary for 6AAK

• Entry DOI: 10.2210/pdb6aak/pdb
• Descriptor: Tyrosine-protein kinase JAK3, 4-[[(1S,3R)-5-oxidanyl-2-adamantyl]amino]-1H-pyrrolo[2,3-b]pyridine-5-carboxamide (3 entities in total)
• Functional Keywords: protein kinase, transferase-inhibitor complex, transferase/inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 4
• Total formula weight: 132739.29

Authors

Amano, Y. (deposition date: 2018-07-18, release date: 2018-08-15, Last modification date: 2024-10-23)

Primary citation

Hamaguchi, H.,Amano, Y.,Moritomo, A.,Shirakami, S.,Nakajima, Y.,Nakai, K.,Nomura, N.,Ito, M.,Higashi, Y.,Inoue, T.
Discovery and structural characterization of peficitinib (ASP015K) as a novel and potent JAK inhibitor
Bioorg. Med. Chem., 26:4971-4983, 2018

PubMed Abstract: Janus kinases (JAKs) are considered promising targets for the treatment of autoimmune diseases including rheumatoid arthritis (RA) due to their important role in multiple cytokine receptor signaling pathways. Recently, several JAK inhibitors have been developed for the treatment of RA. Here, we describe the identification of the novel orally bioavailable JAK inhibitor 18, peficitinib (also known as ASP015K), which showed moderate selectivity for JAK3 over JAK1, JAK2, and TYK2 in enzyme assays. Chemical modification at the C4-position of lead compound 5 led to a large increase in JAK inhibitory activity and metabolic stability in liver microsomes. Furthermore, we determined the crystal structures of JAK1, JAK2, JAK3, and TYK2 in a complex with peficitinib, and revealed that the 1H-pyrrolo[2,3-b]pyridine-5-carboxamide scaffold of peficitinib forms triple hydrogen bonds with the hinge region. Interestingly, the binding modes of peficitinib in the ATP-binding pockets differed among JAK1, JAK2, JAK3, and TYK2. WaterMap analysis of the crystal structures suggests that unfavorable water molecules are the likely reason for the difference in orientation of the 1H-pyrrolo[2,3-b]pyridine-5-carboxamide scaffold to the hinge region among JAKs.

PubMed: 30145050
DOI: 10.1016/j.bmc.2018.08.005

Experimental method

X-RAY DIFFRACTION (2.67 Å)