Advances in the structural biology, design and clinical development of VEGF-R kinase inhibitors for the treatment of angiogenesis

Manley, Paul W.; Bold, Guido; Brüggen, Josef; Fendrich, Gabriele; Furet, Pascal; Mestan, Jürgen; Schnell, Christian; Stolz, Barbara; Meyer, Thomas; Meyhack, Bernd; Stark, Wilhelm; Strauss, André; Wood, Jeanette M.

doi:10.1016/j.bbapap.2003.11.010

Cited by 140 publications

(110 citation statements)

References 31 publications

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“…To abrogate VEGF receptor (VEGFR) activation on demand we employed a dose of the highly specific tyrosine kinase inhibitor SU5416 that completely blocks primary Se angiogenesis even when VEGF signaling is enhanced (Mendel et al, 2000;Zygmunt et al, 2011). SU5416 abrogates the signaling activity of VEGFR1/Flt1 (Itokawa et al, 2002), VEGFR2/KDR (Mendel et al, 2000) and VEGFR3/Flt4 (Manley et al, 2004). All three VEGF receptors are implicated in the formation of the trunk vasculature (see Habeck et al, 2002;Covassin et al, 2006;Siekmann and Lawson, 2007;Hogan et al, 2009b;Krueger et al, 2011;Zygmunt et al, 2011).…”

Section: Characterization Of Circulatory Flow During Dlav Plexus Morpmentioning

confidence: 99%

In parallelinterconnectivity of the dorsal longitudinal anastomotic vessels requires both VEGF signaling and circulatory flow

Zygmunt

Trzaska

Edelstein

et al. 2012

Journal of Cell Science

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SummaryBlood vessels deliver oxygen, nutrients, hormones and immunity factors throughout the body. To perform these vital functions, vascular cords branch, lumenize and interconnect. Yet, little is known about the cellular, molecular and physiological mechanisms that control how circulatory networks form and interconnect. Specifically, how circulatory networks merge by interconnecting 'in parallel' along their boundaries remains unexplored. To examine this process we studied the formation and functional maturation of the plexus that forms between the dorsal longitudinal anastomotic vessels (DLAVs) in the zebrafish. We find that the migration and proliferation of endothelial cells within the DLAVs and their segmental (Se) vessel precursors drives DLAV plexus formation. Remarkably, the presence of Se vessels containing only endothelial cells of the arterial lineage is sufficient for DLAV plexus morphogenesis, suggesting that endothelial cells from the venous lineage make a dispensable or null contribution to this process. The discovery of a circuit that integrates the inputs of circulatory flow and vascular endothelial growth factor (VEGF) signaling to modulate aortic arch angiogenesis, together with the expression of components of this circuit in the trunk vasculature, prompted us to investigate the role of these inputs and their relationship during DLAV plexus formation. We find that circulatory flow and VEGF signaling make additive contributions to DLAV plexus morphogenesis, rather than acting as essential inputs with equivalent contributions as they do during aortic arch angiogenesis. Our observations underscore the existence of context-dependent differences in the integration of physiological stimuli and signaling cascades during vascular development.

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Section: Characterization Of Circulatory Flow During Dlav Plexus Morpmentioning

confidence: 99%

In parallelinterconnectivity of the dorsal longitudinal anastomotic vessels requires both VEGF signaling and circulatory flow

Zygmunt

Trzaska

Edelstein

et al. 2012

Journal of Cell Science

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“…They often are dysregulated, mutated, or overexpressed in human malignancies. [3][4][5] Imatinib mesylate was the first in this class to demonstrate clinical benefit [6][7][8] . It was designed originally to inhibit the activity of bcr-abl, the fusion gene product that transforms and drives chronic myelogenous leukemia 8 .…”

mentioning

confidence: 99%

A prospective analysis of imatinib‐induced c‐kit modulation in ovarian cancer

Posadas

Kwitkowski²,

Kotz³

et al. 2007

Cancer

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The morphology of the telencephalon displays great diversity among different vertebrate lineages. Particularly the everted telencephalon of ray‐finned fishes shows a noticeably different morphology from the evaginated telencephalon of nonray‐finned fishes and other vertebrates. This makes the comparison between the different parts of the telencephalon of ray‐finned fishes and other vertebrates difficult. Based on neuroanatomical, neurochemical, and connectional data no consensus on the subdivisions of the adult telencephalon of ray‐finned fishes and their relation to nuclei in the telencephalon of other vertebrates has been reached yet. For tetrapods, comparative expression pattern analysis of homologous developmental genes has been a successful approach to clarify homologies between different parts of the telencephalon. In the larval zebrafish, subdivisions of the subpallium have been proposed using conserved developmental gene expression. In this study, we investigate the subdivisions of the adult zebrafish telencephalon by analyzing the expression pattern of conserved molecular marker genes. We identify the boundary between the pallium and subpallium based on the complementary expression of dlx2a, dlx5a in the subpallium and tbr1, neurod in the pallium. Furthermore, combinatorial expression of Isl, nkx2.1b, lhx1b, tbr1, eomesa, emx1, emx2, and emx3 identifies striatal‐like, pallidal‐like, and septal‐like subdivisions within the subpallium. In contrast to previous models, we propose that the striatum and pallidum are stretched along the rostrocaudal axis of the telencephalon. Further, the septal nuclei derive from both the pallium and subpallium. On this basis, we present a new model for the subdivisions of the subpallium in teleost fish. J. Comp. Neurol. 520:633–655, 2012. © 2011 Wiley Periodicals, Inc.

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“…Some degree of skepticism towards the potential of anti-angiogenic cancer therapy arose from disappointing results in early clinical trials, but new clinical data with recently developed agents have provided a proof of concept for this therapy. 4,5 In a previous study, we found that 4-[(N-imidazol-2-ylmethyl)-4-chloroanilino]benzopyran compound 1 ( Fig. 1) strongly inhibited HUVEC tube formation and significantly inhibited tumor growth by 52% on A549 (human non small cell lung carcinoma) in nude mice xenografts without any significant side effects by oral administration.…”

Section: Introductionmentioning

confidence: 99%

4-[(N-Imidazol-2-ylmethyl)anilino]pyranopyridine Analogs as Novel Anti-Angiogenic Agents

2005

Bulletin of the Korean Chemical Society

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(imidazol-2-ylmethyl)aniline moiety at the 4-position, were synthesized respectively, and evaluated for primary anti-angiogenic properties through primary cultured HUVEC tube formation assay. From this study, we found that the pyranopyridine ring, especially [3,2-b]-and [2,3-c]-isomer, can replace the benzopyran ring of the compound 1 and can be optimized through the introduction of substituents both on the pyranopyridine ring and the aniline moiety for the identification of a novel anti-angiogenic agent.

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Advances in the structural biology, design and clinical development of VEGF-R kinase inhibitors for the treatment of angiogenesis

Cited by 140 publications

References 31 publications

In parallelinterconnectivity of the dorsal longitudinal anastomotic vessels requires both VEGF signaling and circulatory flow

In parallelinterconnectivity of the dorsal longitudinal anastomotic vessels requires both VEGF signaling and circulatory flow

A prospective analysis of imatinib‐induced c‐kit modulation in ovarian cancer

4-[(N-Imidazol-2-ylmethyl)anilino]pyranopyridine Analogs as Novel Anti-Angiogenic Agents

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