7APF

Crystal structure of JAK3 in complex with FM601 (compound 10a)

7APF の概要

• エントリーDOI: 10.2210/pdb7apf/pdb
• 分子名称: Tyrosine-protein kinase JAK3, 3-[3-(propanoylamino)phenyl]-1~{H}-pyrrolo[2,3-b]pyridine-5-carboxamide, 1-phenylurea, ... (5 entities in total)
• 機能のキーワード: kinase, jak3, inhibitor, covalent inhibitor, structural genomics, structural genomics consortium, sgc, 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: 68220.08

構造登録者

Chaikuad, A.,Forster, M.,Gehringer, M.,Laufer, S.,Knapp, S.,Structural Genomics Consortium (SGC) (登録日: 2020-10-16, 公開日: 2020-12-02, 最終更新日: 2024-01-31)

主引用文献

Forster, M.,Liang, X.J.,Schroder, M.,Gerstenecker, S.,Chaikuad, A.,Knapp, S.,Laufer, S.,Gehringer, M.
Discovery of a Novel Class of Covalent Dual Inhibitors Targeting the Protein Kinases BMX and BTK.
Int J Mol Sci, 21:-, 2020

PubMed Abstract: The nonreceptor tyrosine TEC kinases are key regulators of the immune system and play a crucial role in the pathogenesis of diverse hematological malignancies. In contrast to the substantial efforts in inhibitor development for Bruton's tyrosine kinase (BTK), specific inhibitors of the other TEC kinases, including the bone marrow tyrosine kinase on chromosome X (BMX), remain sparse. Here we present a novel class of dual BMX/BTK inhibitors, which were designed from irreversible inhibitors of Janus kinase (JAK) 3 targeting a cysteine located within the solvent-exposed front region of the ATP binding pocket. Structure-guided design exploiting the differences in the gatekeeper residues enabled the achievement of high selectivity over JAK3 and certain other kinases harboring a sterically demanding residue at this position. The most active compounds inhibited BMX and BTK with apparent IC values in the single digit nanomolar range or below showing moderate selectivity within the TEC family and potent cellular target engagement. These compounds represent an important first step towards selective chemical probes for the protein kinase BMX.

PubMed: 33291717
DOI: 10.3390/ijms21239269

実験手法

X-RAY DIFFRACTION (1.95 Å)