8BX9

Crystal structure of JAK2 JH1 in complex with ilginatinib

8BX9 の概要

• エントリーDOI: 10.2210/pdb8bx9/pdb
• 分子名称: Tyrosine-protein kinase JAK2, Ilginatinib, DIMETHYL SULFOXIDE, ... (4 entities in total)
• 機能のキーワード: janus kinase, inhibitor complex, jak2, jh1, transferase
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 75471.69

構造登録者

Haikarainen, T. (登録日: 2022-12-08, 公開日: 2023-12-20, 最終更新日: 2024-07-10)

主引用文献

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

実験手法

X-RAY DIFFRACTION (1.4 Å)