4ZSA

Crystal structure of FGFR1 kinase domain in complex with 7n

Summary for 4ZSA

• Entry DOI: 10.2210/pdb4zsa/pdb
• Descriptor: Fibroblast growth factor receptor 1, 4-(4-ethylpiperazin-1-yl)-N-[6-(3-methoxyphenyl)-2H-indazol-3-yl]benzamide (3 entities in total)
• Functional Keywords: fgfr1 inhibitor, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (Human)
• Cellular location: Cell membrane; Single-pass type I membrane protein: P11362
• Total number of polymer chains: 2
• Total formula weight: 71067.67

Authors

Liu, Q.F.,Xu, Y.C. (deposition date: 2015-05-13, release date: 2015-06-17, Last modification date: 2023-11-08)

Primary citation

Liu, J.,Peng, X.,Dai, Y.,Zhang, W.,Ren, S.,Ai, J.,Geng, M.,Li, Y.
Design, synthesis and biological evaluation of novel FGFR inhibitors bearing an indazole scaffold.
Org.Biomol.Chem., 13:7643-7654, 2015

PubMed Abstract: Fibroblast growth factor receptor (FGFR) is a potential target for cancer therapy. Based on the structure of AZD4547 and NVPBGJ-398, we designed novel 1H-indazol-3-amine scaffold derivatives by utilizing scaffold hopping and molecular hybridization strategies. Consequently, twenty-eight new compounds were synthesized and evaluated for their inhibitory activity against FGFR1. Compound 7n bearing a 6-(3-methoxyphenyl)-1H-indazol-3-amine scaffold was first identified as a potent FGFR1 inhibitor, with good enzymatic inhibition (IC50 = 15.0 nM) and modest cellular inhibition (IC50 = 642.1 nM). The crystal structure of 7n bound to FGFR1 was obtained, which might provide a new basis for potent inhibitor design. Further structural optimization revealed that compound 7r stood out as the most potent FGFR1 inhibitor with the best enzyme inhibitory (IC50 = 2.9 nM) and cellular activity (IC50 = 40.5 nM).

PubMed: 26080733
DOI: 10.1039/c5ob00778j

Experimental method

X-RAY DIFFRACTION (2 Å)