title: Advances in the structural biology, design and clinical development of VEGF-R kinase inhibitors for the treatment of angiogenesis.
abstract: Initial studies with angiogenesis inhibitors showed little clinical benefit. However, recently reported clinical studies in colorectal cancer have shown that bevacizumab, a vascular endothelial growth factor (VEGF) monoclonal antibody, in combination with cytotoxic therapy has positive effects on patient survival. Furthermore, the VEGF receptor kinase (VEGF-R) tyrosine kinase inhibitor, vatalanib, has also shown encouraging results in colorectal cancer, with molecular resonance imaging providing evidence that the anti-tumor efficacy was indeed the result of anti-angiogenic activity. Both of these agents are progressing in phase III trials. This proof of concept has stimulated the desire for second-generation VEGF-R inhibitors having an improved profile. Structural biology insight regarding the binding mode of protein kinase inhibitors is valuable for the design of molecules possessing superior selectivity, efficacy and tolerability. Towards this goal, we have developed a new series of VEGF-R2 kinase inhibitors, based upon an anthranilic acid amide scaffold. An X-ray crystal structure of a representative compound, AAL993 (ZK260253), in complex with the catalytic domain of diphosphorylated VEGF-R2 has revealed that this molecule binds to an inactive conformation of the protein. This binding mode, similar to that observed for the anti-leukemia drug, imatinib in complex with c-Abl kinase, may be responsible for the high selectivity of AAL993 and provides valuable insight for the design of further compounds.
authors.affiliation: Novartis Institutes of Biomedical Research, WKL-136-4-86, CH-4002 Basel, Switzerland. paul.manley@pharma.norvartis.com
authors.forename: Paul William
authors.initials: PW
authors.lastname: Manley
authors.forename: Guido
authors.initials: G
authors.lastname: Bold
authors.forename: Josef
authors.initials: J
authors.lastname: Brüggen
authors.forename: Gabrielle
authors.initials: G
authors.lastname: Fendrich
authors.forename: Pascal
authors.initials: P
authors.lastname: Furet
authors.forename: Jürgen
authors.initials: J
authors.lastname: Mestan
authors.forename: Christian
authors.initials: C
authors.lastname: Schnell
authors.forename: Barbara
authors.initials: B
authors.lastname: Stolz
authors.forename: Thomas
authors.initials: T
authors.lastname: Meyer
authors.forename: Bernd
authors.initials: B
authors.lastname: Meyhack
authors.forename: Wilhelm
authors.initials: W
authors.lastname: Stark
authors.forename: Andre
authors.initials: A
authors.lastname: Strauss
authors.forename: Jeanette
authors.initials: J
authors.lastname: Wood
mesh_terms: D020533:Angiogenesis Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D002986:Clinical Trials as Topic; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D008958:Models, Molecular; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D011485:Protein Binding; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*
chemical_list: D020533:Angiogenesis Inhibitors; D004791:Enzyme Inhibitors; D040262:Receptors, Vascular Endothelial Growth Factor