5HX8

Jak1 complex with 4-[(4-aminocyclohexyl)amino]-3-(1H-benzimidazol-2-yl)-1H-pyridin-2-one

Summary for 5HX8

• Entry DOI: 10.2210/pdb5hx8/pdb
• Descriptor: Tyrosine-protein kinase JAK1, 4-[(4-aminocyclohexyl)amino]-3-(1H-benzimidazol-2-yl)-1H-pyridin-2-one (3 entities in total)
• Functional Keywords: kinase, inhibitor, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (Human)
• Cellular location: Endomembrane system; Peripheral membrane protein: P23458
• Total number of polymer chains: 2
• Total formula weight: 70139.97

Authors

Su, H.P. (deposition date: 2016-01-29, release date: 2016-03-16, Last modification date: 2024-10-23)

Primary citation

Simov, V.,Deshmukh, S.V.,Dinsmore, C.J.,Elwood, F.,Fernandez, R.B.,Garcia, Y.,Gibeau, C.,Gunaydin, H.,Jung, J.,Katz, J.D.,Kraybill, B.,Lapointe, B.,Patel, S.B.,Siu, T.,Su, H.,Young, J.R.
Structure-based design and development of (benz)imidazole pyridones as JAK1-selective kinase inhibitors.
Bioorg.Med.Chem.Lett., 26:1803-1808, 2016

PubMed Abstract: The mammalian Janus Kinases (JAK1, JAK2, JAK3 and TYK2) are intracellular, non-receptor tyrosine kinases whose activities have been associated in the literature and the clinic with a variety of hyperproliferative diseases and immunological disorders. At the onset of the program, it was hypothesized that a JAK1 selective compound over JAK2 could lead to an improved therapeutic index relative to marketed non-selective JAK inhibitors by avoiding the clinical AEs, such as anemia, presumably associated with JAK2 inhibition. During the course of the JAK1 program, a number of diverse chemical scaffolds were identified from both uHTS campaigns and de novo scaffold design. As part of this effort, a (benz)imidazole scaffold evolved via a scaffold-hopping exercise from a mature chemical series. Concurrent crystallography-driven exploration of the ribose pocket and the solvent front led to analogs with optimized kinome and JAK1 selectivities over the JAK2 isoform by targeting several residues unique to JAK1, such as Arg-879 and Glu-966.

PubMed: 26927423
DOI: 10.1016/j.bmcl.2016.02.035

Experimental method

X-RAY DIFFRACTION (2.2 Å)