7DHL
Crystal structure of FGFR3 in complex with pyrimidine derivative
Summary for 7DHL
| Entry DOI | 10.2210/pdb7dhl/pdb |
| Descriptor | Fibroblast growth factor receptor 3, 5-[2-(3,5-dimethoxyphenyl)ethyl]-N-[3-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl]pyrimidin-2-amine (3 entities in total) |
| Functional Keywords | protein kinase, signaling protein, transferase |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 1 |
| Total formula weight | 36211.44 |
| Authors | Echizen, Y.,Tateishi, Y.,Amano, Y. (deposition date: 2020-11-16, release date: 2021-02-03, Last modification date: 2024-11-06) |
| Primary citation | Kuriwaki, I.,Kameda, M.,Iikubo, K.,Hisamichi, H.,Kawamoto, Y.,Kikuchi, S.,Moritomo, H.,Kondoh, Y.,Terasaka, T.,Amano, Y.,Tateishi, Y.,Echizen, Y.,Iwai, Y.,Noda, A.,Tomiyama, H.,Nakazawa, T.,Hirano, M. Synthesis and structure-activity relationships of pyrimidine derivatives as potent and orally active FGFR3 inhibitors with both increased systemic exposure and enhanced in vitro potency. Bioorg.Med.Chem., 33:116019-116019, 2021 Cited by PubMed Abstract: Fibroblast growth factor receptor 3 (FGFR3) is an attractive therapeutic target for the treatment of patients with bladder cancer harboring genetic alterations in FGFR3. We identified pyrimidine derivative 20b, which induced tumor regression following oral administration to a bladder cancer xenograft mouse model. Compound 20b was discovered by optimizing lead compound 1, which we reported previously. Specifically, reducing the molecular size of the substituent at the 4-position and replacing the linker of the 5-position in the pyrimidine scaffold resulted in an increase in systemic exposure. Furthermore, introduction of two fluorine atoms into the 3,5-dimethoxyphenyl ring enhanced FGFR3 inhibitory activity. Molecular dynamics (MD) simulation of 20b suggested that the fluorine atom interacts with the main chain NH moiety of Asp635 via a hydrogen bond. PubMed: 33486159DOI: 10.1016/j.bmc.2021.116019 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.57 Å) |
Structure validation
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