6N6O
Crystal structure of the human TTK in complex with an inhibitor
Summary for 6N6O
| Entry DOI | 10.2210/pdb6n6o/pdb |
| Related | 6B4W |
| Descriptor | Dual specificity protein kinase TTK, 4-({5-chloro-4-[(cis-4-hydroxy-4-methylcyclohexyl)oxy]-7H-pyrrolo[2,3-d]pyrimidin-2-yl}amino)-N,N-dimethyl-3-{[(2R)-1,1,1-trifluoropropan-2-yl]oxy}benzamide, PENTAETHYLENE GLYCOL, ... (5 entities in total) |
| Functional Keywords | protein kinase activity protein serine/threonine/tyrosine kinase activity atp binding protein phosphorylation mitotic cell cycle checkpoint chromosome separation, signaling protein |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 1 |
| Total formula weight | 33783.12 |
| Authors | Fenalti, G. (deposition date: 2018-11-26, release date: 2019-05-15, Last modification date: 2024-10-30) |
| Primary citation | Riggs, J.R.,Elsner, J.,Cashion, D.,Robinson, D.,Tehrani, L.,Nagy, M.,Fultz, K.E.,Krishna Narla, R.,Peng, X.,Tran, T.,Kulkarni, A.,Bahmanyar, S.,Condroski, K.,Pagarigan, B.,Fenalti, G.,LeBrun, L.,Leftheris, K.,Zhu, D.,Boylan, J.F. Design and Optimization Leading to an Orally Active TTK Protein Kinase Inhibitor with Robust Single Agent Efficacy. J.Med.Chem., 62:4401-4410, 2019 Cited by PubMed Abstract: Triple negative breast cancer (TNBC) is an aggressive disease with high relapse rates and few treatment options. Outlined in previous publications, we identified a series of potent, dual TTK/CLK2 inhibitors with strong efficacy in TNBC xenograft models. Pharmacokinetic properties and kinome selectivity were optimized, resulting in the identification of a new series of potent, selective, and orally bioavailable TTK inhibitors. We describe here the structure-activity relationship of the 2,4-disubstituted-7 H-pyrrolo[2,3- d]pyrimidine series, leading to significant single agent efficacy in a TNBC xenograft model without body weight loss. The design effort evolving an iv-dosed TTK/CLK2 inhibitor to an orally bioavailable TTK inhibitor is described. PubMed: 30998356DOI: 10.1021/acs.jmedchem.8b01869 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.6 Å) |
Structure validation
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