9FLT

Crystal structure of human Haspin (GSG2) kinase bound to chemical probe MU1920

これはPDB形式変換不可エントリーです。

9FLT の概要

• エントリーDOI: 10.2210/pdb9flt/pdb
• 分子名称: Serine/threonine-protein kinase haspin, ~{N}-(1,4-dimethylpyrazol-3-yl)-3-pyridin-4-yl-thieno[3,2-b]pyridin-5-amine, NICKEL (II) ION, ... (4 entities in total)
• 機能のキーワード: haspin, kinase, chemical probe, 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: 1
• 化学式量合計: 38619.93

構造登録者

Kraemer, A.,Paruch, K.,Knapp, S.,Structural Genomics Consortium (SGC) (登録日: 2024-06-05, 公開日: 2024-09-11, 最終更新日: 2025-03-26)

主引用文献

Moyano, P.M.,Kubina, T.,Paruch, S.O.,Jaroskova, A.,Novotny, J.,Skockova, V.,Ovesna, P.,Suchankova, T.,Prokofeva, P.,Kuster, B.,Smida, M.,Chaikuad, A.,Kramer, A.,Knapp, S.,Soucek, K.,Paruch, K.
Thieno[3,2-b]pyridine: Attractive scaffold for highly selective inhibitors of underexplored protein kinases with variable binding mode.
Angew.Chem.Int.Ed.Engl., 64:e202412786-e202412786, 2025

PubMed Abstract: Protein kinases are key regulators of numerous biological processes and aberrant kinase activity can cause various diseases, particularly cancer. Herein, we report the identification of new series of highly selective kinase inhibitors based on the thieno[3,2-b]pyridine scaffold. The weak interaction of the thieno[3,2-b]pyridine core with the kinase hinge region allows for profoundly different binding modes all of which maintain high kinome-wide selectivity, as illustrated by the isomers MU1464 and MU1668. Thus, this core structure provides a template of ATP-competitive but not ATP-mimetic inhibitors that are anchored at the kinase back pocket. Mapping the chemical space around the central thieno[3,2-b]pyridine pharmacophore afforded highly selective inhibitors of the kinase Haspin, exemplified by the compound MU1920 that fulfils criteria for a quality chemical probe and is suitable for use in in vivo applications. However, despite the role of Haspin in mitosis, the inhibition of Haspin alone was not sufficient to elicit cytotoxic effect in cancer cells. The thieno[3,2-b]pyridine scaffold can be used in a broader context, as a basis of inhibitors targeting other underexplored protein kinases, such as CDKLs.

PubMed: 39503260
DOI: 10.1002/anie.202412786

実験手法

X-RAY DIFFRACTION (2.4 Å)