6YAT
Crystal structure of STK4 (MST1) in complex with compound 6
Summary for 6YAT
| Entry DOI | 10.2210/pdb6yat/pdb |
| Descriptor | Serine/threonine-protein kinase 4, (2R)-3-(cyclohexylamino)-2-hydroxypropane-1-sulfonic acid, GLYCEROL, ... (5 entities in total) |
| Functional Keywords | kinase, kinase inhibitor, mst1, stk4, hippo pathway, chemical probe, structural genomics, structural genomics consortium, sgc, transferase |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 2 |
| Total formula weight | 73135.32 |
| Authors | Chaikuad, A.,Bata, N.,Limpert, A.S.,Lambert, L.J.,Bakas, N.A.,Cosford, N.D.P.,Knapp, S.,Structural Genomics Consortium (SGC) (deposition date: 2020-03-13, release date: 2020-04-29, Last modification date: 2024-10-23) |
| Primary citation | Bata, N.,Chaikuad, A.,Bakas, N.A.,Limpert, A.S.,Lambert, L.J.,Sheffler, D.J.,Berger, L.M.,Liu, G.,Yuan, C.,Wang, L.,Peng, Y.,Dong, J.,Celeridad, M.,Layng, F.,Knapp, S.,Cosford, N.D.P. Inhibitors of the Hippo Pathway Kinases STK3/MST2 and STK4/MST1 Have Utility for the Treatment of Acute Myeloid Leukemia. J.Med.Chem., 65:1352-1369, 2022 Cited by PubMed Abstract: Serine/threonine-protein kinases 3 and 4 (STK3 and STK4, respectively) are key components of the Hippo signaling pathway, which regulates cell proliferation and death and provides a potential therapeutic target for acute myeloid leukemia (AML). Herein, we report the structure-based design of a series of pyrrolopyrimidine derivatives as STK3 and STK4 inhibitors. In an initial screen, the compounds exhibited low nanomolar potency against both STK3 and STK4. Crystallization of compound with STK4 revealed two-point hinge binding in the ATP-binding pocket. Further characterization and analysis demonstrated that compound (SBP-3264) specifically inhibited the Hippo signaling pathway in cultured mammalian cells and possessed favorable pharmacokinetic and pharmacodynamic properties in mice. We show that genetic knockdown and pharmacological inhibition of STK3 and STK4 suppress the proliferation of AML cells in vitro. Thus, SBP-3264 is a valuable chemical probe for understanding the roles of STK3 and STK4 in AML and is a promising candidate for further advancement as a potential therapy. PubMed: 34807584DOI: 10.1021/acs.jmedchem.1c00804 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.58 Å) |
Structure validation
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