7OZB
FGFR1 kinase domain (residues 458-765) with mutations C488A, C584S in complex with 38.
This is a non-PDB format compatible entry.
Summary for 7OZB
| Entry DOI | 10.2210/pdb7ozb/pdb |
| Descriptor | Fibroblast growth factor receptor 1, 4-[3-(4-piperazin-4-ium-1-ylphenyl)-1H-indazol-6-yl]phenol, SULFATE ION, ... (5 entities in total) |
| Functional Keywords | fgfr1, inhibitor, receptor tyrosine kinase, transferase |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 2 |
| Total formula weight | 71990.45 |
| Authors | Trinh, C.H.,Turner, L.D.,Fishwick, C.W.G. (deposition date: 2021-06-27, release date: 2021-12-01, Last modification date: 2024-01-31) |
| Primary citation | Turner, L.D.,Trinh, C.H.,Hubball, R.A.,Orritt, K.M.,Lin, C.C.,Burns, J.E.,Knowles, M.A.,Fishwick, C.W.G. From Fragment to Lead: De Novo Design and Development toward a Selective FGFR2 Inhibitor. J.Med.Chem., 65:1481-1504, 2022 Cited by PubMed Abstract: Fibroblast growth factor receptors (FGFRs) are implicated in a range of cancers with several pan-kinase and selective-FGFR inhibitors currently being evaluated in clinical trials. Pan-FGFR inhibitors often cause toxic side effects and few examples of subtype-selective inhibitors exist. Herein, we describe a structure-guided approach toward the development of a selective FGFR2 inhibitor. De novo design was carried out on an existing fragment series to yield compounds predicted to improve potency against the FGFRs. Subsequent iterative rounds of synthesis and biological evaluation led to an inhibitor with nanomolar potency that exhibited moderate selectivity for FGFR2 over FGFR1/3. Subtle changes to the lead inhibitor resulted in a complete loss of selectivity for FGFR2. X-ray crystallographic studies revealed inhibitor-specific morphological differences in the P-loop which were posited to be fundamental to the selectivity of these compounds. Additional docking studies have predicted an FGFR2-selective H-bond which could be utilized to design more selective FGFR2 inhibitors. PubMed: 34780700DOI: 10.1021/acs.jmedchem.1c01163 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.71 Å) |
Structure validation
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