9FLC
Crystal structure of haspin (GSG2) in complex with MU1668
This is a non-PDB format compatible entry.
Summary for 9FLC
| Entry DOI | 10.2210/pdb9flc/pdb |
| Descriptor | Serine/threonine-protein kinase haspin, 5-(1-methylpyrazol-3-yl)-3-pyridin-4-yl-thieno[3,2-b]pyridine, (4S)-2-METHYL-2,4-PENTANEDIOL, ... (5 entities in total) |
| Functional Keywords | kinase, haspin, inhibitor, structural genomics, structural genomics consortium, sgc, transferase |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 1 |
| Total formula weight | 41214.11 |
| Authors | Chaikuad, A.,Paruch, K.,Knapp, S.,Structural Genomics Consortium (SGC) (deposition date: 2024-06-04, release date: 2024-09-11, Last modification date: 2025-03-26) |
| Primary citation | 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 Cited by 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: 39503260DOI: 10.1002/anie.202412786 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.18 Å) |
Structure validation
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