7ZKS

SRPK1 IN COMPLEX WITH INHIBITOR

7ZKS の概要

• エントリーDOI: 10.2210/pdb7zks/pdb
• 分子名称: SRSF protein kinase 1, N-[3-[[[2-(6-chloranyl-5-fluoranyl-1H-benzimidazol-2-yl)pyrimidin-4-yl]amino]methyl]pyridin-2-yl]-N-methyl-methanesulfonamide, CHLORIDE ION, ... (4 entities in total)
• 機能のキーワード: serine/threonine-protein kinase, srpk1, nuclear protein, transferase
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 44582.76

構造登録者

Graedler, U. (登録日: 2022-04-13, 公開日: 2023-02-22, 最終更新日: 2024-02-07)

主引用文献

Schroder, M.,Leiendecker, M.,Gradler, U.,Braun, J.,Blum, A.,Wanior, M.,Berger, B.T.,Kramer, A.,Muller, S.,Esdar, C.,Knapp, S.,Heinrich, T.
MSC-1186, a Highly Selective Pan-SRPK Inhibitor Based on an Exceptionally Decorated Benzimidazole-Pyrimidine Core.
J.Med.Chem., 66:837-854, 2023

PubMed Abstract: The highly conserved catalytic sites in protein kinases make it difficult to identify ATP competitive inhibitors with kinome-wide selectivity. Serendipitously, during a dedicated fragment campaign for the focal adhesion kinase (FAK), a scaffold that had lost its initial FAK affinity showed remarkable potency and selectivity for serine-arginine-protein kinases 1-3 (SRPK1-3). Non-conserved interactions with the uniquely structured hinge region of the SRPK family were the key drivers of the exclusive selectivity of the discovered fragment hit. Structure-guided medicinal chemistry efforts led to the SRPK inhibitor , which fulfills all hallmarks of a reversible chemical probe, including nanomolar cellular potency and excellent kinome-wide selectivity. The combination of with CDC2-like kinase (CLK) inhibitors showed additive attenuation of SR-protein phosphorylation compared to the single agents. and negative control () are chemical probes available via the Structural Genomics Consortium chemical probe program (https://www.sgc-ffm.uni-frankfurt.de/).

PubMed: 36516476
DOI: 10.1021/acs.jmedchem.2c01705

実験手法

X-RAY DIFFRACTION (2.28 Å)