7LQD
Structure of Human MPS1 (TTK) covalently bound to RMS-07 inhibitor
Summary for 7LQD
| Entry DOI | 10.2210/pdb7lqd/pdb |
| Descriptor | Dual specificity protein kinase TTK or monopolar spindle 1 kinase, ~{N}-(2,6-diethylphenyl)-2-[[4-(4-methylpiperazin-1-yl)-2-(propanoylamino)phenyl]amino]-5,6-dihydropyrimido[4,5-e]indolizine-7-carboxamide, GLYCEROL, ... (5 entities in total) |
| Functional Keywords | protein kinase, inhibitor, transferase-transferase inhibitor complex, transferase/transferase inhibitor |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 1 |
| Total formula weight | 37346.69 |
| Authors | Santiago, A.S.,dos Reis, C.V.,Serafim, R.A.M.,Massirer, K.B.,Arruda, P.,Edwards, A.M.,Counago, R.M.,Structural Genomics Consortium (SGC) (deposition date: 2021-02-13, release date: 2022-02-16, Last modification date: 2024-10-23) |
| Primary citation | M Serafim, R.A.,da Silva Santiago, A.,Schwalm, M.P.,Hu, Z.,Dos Reis, C.V.,Takarada, J.E.,Mezzomo, P.,Massirer, K.B.,Kudolo, M.,Gerstenecker, S.,Chaikuad, A.,Zender, L.,Knapp, S.,Laufer, S.,Counago, R.M.,Gehringer, M. Development of the First Covalent Monopolar Spindle Kinase 1 (MPS1/TTK) Inhibitor. J.Med.Chem., 65:3173-3192, 2022 Cited by PubMed Abstract: Monopolar spindle kinase 1 (MPS1/TTK) is a key element of the mitotic checkpoint and clinically evaluated as a target in the treatment of aggressive tumors such as triple-negative breast cancer. While long drug-target residence times have been suggested to be beneficial in the context of therapeutic MPS1 inhibition, no irreversible inhibitors have been reported. Here we present the design and characterization of the first irreversible covalent MPS1 inhibitor, , targeting a poorly conserved cysteine in the kinase's hinge region. shows potent MPS1 inhibitory activity and selectivity against all protein kinases with an equivalent cysteine but also in a broader kinase panel. We demonstrate potent cellular target engagement and pronounced activity against various cancer cell lines. The covalent binding mode was validated by mass spectrometry and an X-ray crystal structure. This proof of MPS1 covalent ligandability may open new avenues for the design of MPS1-specific chemical probes or drugs. PubMed: 35167750DOI: 10.1021/acs.jmedchem.1c01165 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.95 Å) |
Structure validation
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