6VNM

JAK2 JH1 in complex with SY5-103

Summary for 6VNM

• Entry DOI: 10.2210/pdb6vnm/pdb
• Descriptor: Tyrosine-protein kinase JAK2, 4-[1-(but-3-en-1-yl)-1H-pyrazol-4-yl]-N-[4-(piperidin-4-yl)phenyl]-7H-pyrrolo[2,3-d]pyrimidin-2-amine (3 entities in total)
• Functional Keywords: janus associated kinase, jak2, kinase domain, jh1, kinase, transferase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 73737.92

Authors

Davis, R.R.,Schonbrunn, E. (deposition date: 2020-01-29, release date: 2021-02-17, Last modification date: 2024-11-13)

Primary citation

Davis, R.R.,Li, B.,Yun, S.Y.,Chan, A.,Nareddy, P.,Gunawan, S.,Ayaz, M.,Lawrence, H.R.,Reuther, G.W.,Lawrence, N.J.,Schonbrunn, E.
Structural Insights into JAK2 Inhibition by Ruxolitinib, Fedratinib, and Derivatives Thereof.
J.Med.Chem., 64:2228-2241, 2021

PubMed Abstract: The discovery that aberrant activity of Janus kinase 2 (JAK2) is a driver of myeloproliferative neoplasms (MPNs) has led to significant efforts to develop small molecule inhibitors for this patient population. Ruxolitinib and fedratinib have been approved for use in MPN patients, while baricitinib, an achiral analogue of ruxolitinib, has been approved for rheumatoid arthritis. However, structural information on the interaction of these therapeutics with JAK2 remains unknown. Here, we describe a new methodology for the large-scale production of JAK2 from mammalian cells, which enabled us to determine the first crystal structures of JAK2 bound to these drugs and derivatives thereof. Along with biochemical and cellular data, the results provide a comprehensive view of the shape complementarity required for chiral and achiral inhibitors to achieve highest activity, which may facilitate the development of more effective JAK2 inhibitors as therapeutics.

PubMed: 33570945
DOI: 10.1021/acs.jmedchem.0c01952

Experimental method

X-RAY DIFFRACTION (2.2 Å)