3VHE

Crystal structure of human VEGFR2 kinase domain with a novel pyrrolopyrimidine inhibitor.

Summary for 3VHE

• Entry DOI: 10.2210/pdb3vhe/pdb
• Descriptor: Vascular endothelial growth factor receptor 2, 1-{2-fluoro-4-[(5-methyl-5H-pyrrolo[3,2-d]pyrimidin-4-yl)oxy]phenyl}-3-[3-(trifluoromethyl)phenyl]urea (3 entities in total)
• Functional Keywords: kinase domain, kinase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Membrane; Single-pass type I membrane protein: P35968
• Total number of polymer chains: 1
• Total formula weight: 41291.26

Authors

Oguro, Y.,Miyamoto, N.,Okada, K.,Takagi, T.,Iwata, H.,Awazu, Y.,Miki, H.,Hori, A.,Kamiyama, K.,Imanura, S. (deposition date: 2011-08-24, release date: 2011-11-02, Last modification date: 2024-03-20)

Primary citation

Oguro, Y.,Miyamoto, N.,Okada, K.,Takagi, T.,Iwata, H.,Awazu, Y.,Miki, H.,Hori, A.,Kamiyama, K.,Imamura, S.
Design, synthesis, and evaluation of 5-methyl-4-phenoxy-5H-pyrrolo[3,2-d]pyrimidine derivatives: novel VEGFR2 kinase inhibitors binding to inactive kinase conformation.
Bioorg.Med.Chem., 18:7260-7273, 2010

PubMed Abstract: We synthesized a series of pyrrolo[3,2-d]pyrimidine derivatives and evaluated their application as type-II inhibitors of vascular endothelial growth factor receptor 2 (VEGFR2) kinase. Incorporation of a diphenylurea moiety at the C4-position of the pyrrolo[3,2-d]pyrimidine core via an oxygen linker resulted in compounds that were potent inhibitors of VEGFR2 kinase. Of these derivatives, compound 20d showed the strongest inhibition of VEGF-stimulated proliferation of human umbilical vein endothelial cells (HUVEC). The co-crystal structure of 20d and VEGFR2 revealed that 20d binds to the inactive form of VEGFR2. Further studies indicated that 20d inhibited VEGFR2 kinase with slow dissociation kinetics and also inhibited PDGFR and Tie-2 kinases. Oral administration of the hydrochloride salt of 20d at 3mg/kg/day showed potent inhibition of tumor growth in a DU145 human prostate cancer cell xenograft nude mouse model.

PubMed: 20833055
DOI: 10.1016/j.bmc.2010.08.017

Experimental method

X-RAY DIFFRACTION (1.55 Å)