8BM2

Crystal structure of JAK2 JH1 in complex with gandotinib

Summary for 8BM2

• Entry DOI: 10.2210/pdb8bm2/pdb
• Descriptor: Tyrosine-protein kinase JAK2, 3-[(4-chloranyl-2-fluoranyl-phenyl)methyl]-2-methyl-~{N}-(5-methyl-1~{H}-pyrazol-3-yl)-8-(morpholin-4-ylmethyl)imidazo[1,2-b]pyridazin-6-amine (3 entities in total)
• Functional Keywords: janus kinase, inhibitor complex, jak2, jh1, transferase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 75590.56

Authors

Miao, Y.,Haikarainen, T. (deposition date: 2022-11-10, release date: 2023-11-22, Last modification date: 2024-07-10)

Primary citation

Miao, Y.,Virtanen, A.,Zmajkovic, J.,Hilpert, M.,Skoda, R.C.,Silvennoinen, O.,Haikarainen, T.
Functional and Structural Characterization of Clinical-Stage Janus Kinase 2 Inhibitors Identifies Determinants for Drug Selectivity.
J.Med.Chem., 67:10012-10024, 2024

PubMed Abstract: Janus kinase 2 (JAK2) plays a critical role in orchestrating hematopoiesis, and its deregulation leads to various blood disorders, most importantly myeloproliferative neoplasms (MPNs). Ruxolitinib, fedratinib, momelotinib, and pacritinib are FDA-/EMA-approved JAK inhibitors effective in relieving symptoms in MPN patients but show variable clinical profiles due to poor JAK selectivity. The development of next-generation JAK2 inhibitors is hampered by the lack of comparative functional analysis and knowledge of the molecular basis of their selectivity. Here, we provide mechanistic profiling of the four approved and six clinical-stage JAK2 inhibitors and connect selectivity data with high-resolution structural and thermodynamic analyses. All of the JAK inhibitors potently inhibited JAK2 activity. Inhibitors differed in their JAK isoform selectivity and potency for erythropoietin signaling, but their general cytokine inhibition signatures in blood cells were comparable. Structural data indicate that high potency and moderate JAK2 selectivity can be obtained by targeting the front pocket of the adenosine 5'-triphosphate-binding site.

PubMed: 38843875
DOI: 10.1021/acs.jmedchem.4c00197

Experimental method

X-RAY DIFFRACTION (1.5 Å)