Summary for 8Y22
| Entry DOI | 10.2210/pdb8y22/pdb |
| Descriptor | Fibroblast growth factor receptor 1, ~{N}-[4-[[4-azanyl-3-(7-methoxy-5-methyl-1-benzothiophen-2-yl)pyrazolo[3,4-d]pyrimidin-1-yl]methyl]phenyl]propanamide, SULFATE ION, ... (4 entities in total) |
| Functional Keywords | fibroblast growth factor receptor 1, transferase |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 2 |
| Total formula weight | 71838.27 |
| Authors | Chen, X.J.,Chen, Y.H. (deposition date: 2024-01-25, release date: 2024-06-26, Last modification date: 2024-10-30) |
| Primary citation | Deng, W.,Chen, X.,Liang, H.,Song, X.,Xiang, S.,Guo, J.,Tu, Z.,Zhou, Y.,Chen, Y.,Lu, X. Design, synthesis and biological evaluation of 5-amino-1H-pyrazole-4-carboxamide derivatives as pan-FGFR covalent inhibitors. Eur.J.Med.Chem., 275:116558-116558, 2024 Cited by PubMed Abstract: The aberrant activation of FGFRs plays a critical role in various cancers, leading to the development of several FGFR inhibitors in clinic. However, the emergence of drug resistance, primarily due to gatekeeper mutations in FGFRs, has limited their clinical efficacy. To address the unmet medical need, a series of 5-amino-1H-pyrazole-4-carboxamide derivatives were designed and synthesized as novel pan-FGFR covalent inhibitors targeting both wild-type and the gatekeeper mutants. The representative compound 10h demonstrated nanomolar activities against FGFR1, FGFR2, FGFR3 and FGFR2 V564F gatekeeper mutant in biochemical assays (IC = 46, 41, 99, and 62 nM). Moreover, 10h also strongly suppressed the proliferation of NCI-H520 lung cancer cells, SNU-16 and KATO III gastric cancer cells with IC values of 19, 59, and 73 nM, respectively. Further X-ray co-crystal structure revealed that 10h irreversibly binds to FGFR1. The study provides a new promising point for anticancer drug development medicated by FGFRs. PubMed: 38870833DOI: 10.1016/j.ejmech.2024.116558 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.792 Å) |
Structure validation
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