Novel anti-VEGF therapeutics

Excessive and chronic vascular leakage in pathologies such as eye diseases leads to edema, tissue ischemia and disease progression. To suppress vascular leakage by blocking vascular endothelial growth factor (VEGF) function is clinically beneficial. However, development of new, topically applied therapeutic options is important as intravitreal injections currently carried out to deliver anti-VEGF therapeutics is expensive and may have serious side effects. VEGF receptor-2 (VEGFR2) activates Src family kinases via binding the T cell specific adaptor (TSAd) to its phosphotyrosine residue Y951. These molecular interactions are required for gap formation at endothelial junctions and vascular leakage. Here, we describe the identification from a high throughput screen, of a small molecular weight inhibitor (LC1) which blocks the interaction between the phosphorylated VEGFR2 kinase domain and TSAd. LC1 binds to TSAd in surface plasmon resonance analysis. In intact cells, LC1 suppresses VEGFR2 kinase activity while if fails to inhibit kinase activity in an in vitro biochemical kinase screen of 35 kinases including VEGFR2. Superfusion of retinal explants blocks vascular leakage from retinal vessels. In conclusion, we have identified a compound which specifically blocks VEGFR2 function in endothelial cells.

Roche P, FrancisLena Claesson-Welsh (author)
Dragoni, SilviaUniversity College London, Institute of Ophtalmology, London, UK,Patric Turowski (author)
Fukuhara, DaisukeLena Claesson-Welsh (author)
Ohlin Sjöström, ElisabetLena CLaesson-Welsh (author)
Sjöberg, ElinLena Claesson-Welsh (author)
Rickards, MarkLena Claesson-Welsh (author)
Lundbäck, ThomasChemical Biology Consortium Sweden, Science for Life Laboratory, Karolinska Institutet, Stockholm, Sweden (author)
Färnegårdh, KatarinaDrug Discovery and Development, Science for Life Laboratory, Karolinska Institutet, Stockholm, and Uppsala University, Uppsala, Sweden (author)
Roos, AnnetteDrug Discovery and Development, Science for Life Laboratory, Karolinska Institutet, Stockholm, and Uppsala University, Uppsala, Sweden (author)
Abdurakhmanov, EldarDrug Discovery and Development, Science for Life Laboratory, Karolinska Institutet, Stockholm, and Uppsala University, Uppsala, Sweden (author)
Ballmer-Hofer, KurtPaul Scherrer Institute, Villigen, Switzerland (author)
Turowski, KurtUniversity College London, Institute of Ophtalmology, London, UK,Patric Turowski (author)
Claesson-Welsh, LenaLena Claesson-Welsh (author)
Lena Claesson-WelshUniversity College London, Institute of Ophtalmology, London, UK (creator_code:org_t)

By the author/editor: Persson Skare, T ...; Roche P, Francis; Dragoni, Silvia; Fukuhara, Daisuk ...; Ohlin Sjöström, ...; Sjöberg, Elin; show more...; Rickards, Mark; Lundbäck, Thomas; Färnegårdh, Kata ...; Roos, Annette; Abdurakhmanov, E ...; Ballmer-Hofer, K ...; Turowski, Kurt; Claesson-Welsh, ...; show less...

About the subject

MEDICAL AND HEALTH SCIENCES: MEDICAL AND HEAL ...; and Basic Medicine; and Cell and Molecul ...

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