8XKP
Crystal structure of human tyrosine-protein kinase Fes/Fps in complex with compound 17c
This is a non-PDB format compatible entry.
Summary for 8XKP
| Entry DOI | 10.2210/pdb8xkp/pdb |
| Descriptor | Tyrosine-protein kinase Fes/Fps, SULFATE ION, 7-[[(1R,2S)-2-azanylcyclohexyl]amino]-5-[[3-[(2S,6R)-2,6-dimethylmorpholin-4-yl]phenyl]amino]-4-oxidanylidene-3H-pyrido[3,4-d]pyridazine-8-carbonitrile, ... (4 entities in total) |
| Functional Keywords | fes, c-fes, tyrosine protein kinase, transferase |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 1 |
| Total formula weight | 43165.36 |
| Authors | Baba, D.,Hanzawa, H. (deposition date: 2023-12-23, release date: 2025-01-01, Last modification date: 2025-03-19) |
| Primary citation | Taniguchi, T.,Yasumatsu, I.,Inagaki, H.,Baba, D.,Toyota, A.,Kaneta, Y.,Odagiri, T.,Momose, T.,Kawai, J.,Imaoka, T.,Nakayama, K. Optimization of Novel Pyrido-pyridazinone Derivatives as FER Tyrosine Kinase Inhibitors, Leading to the Potent DS08701581. Acs Med.Chem.Lett., 15:1010-1016, 2024 Cited by PubMed Abstract: Previously, we reported the new pyrido-pyridazinone template as a feline sarcoma-related (FER) tyrosine kinase inhibitor. Representative compound () showed strong enzyme inhibitory activity (IC50 = 0.5 nM), however, its antitumor effect was insufficient, probably due to poor solubility and resultant low bioavailability (BA). In addition, the kinase selectivity was inadequate, which may result in certain safety risks. Here, we focused on derivatization of the unoptimized C-5 position to obtain promising FER inhibitors possessing strong antitumor effects and improved selectivity, referring to their X-ray crystal structure and the docking model with FES proto-oncogene tyrosine kinase as an FER surrogate. While establishing the synthetic route of the pyrido-pyridazinone scaffold, we obtained a desired compound via our derivatization. Our optimized compound ) showed the highest class cell-free and cell activities in this template, good oral BA, and improved kinase selectivity, resulting in significant tumor growth inhibition in the Ba/F3-FER tumor model without body weight loss. PubMed: 39015278DOI: 10.1021/acsmedchemlett.4c00030 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.05 Å) |
Structure validation
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