New Anilinophthalazines as Potent and Orally Well Absorbed Inhibitors of the VEGF Receptor Tyrosine Kinases Useful as Antagonists of Tumor-Driven Angiogenesis

Bold, Guido; Kh, Altmann; Frei, Joerg; Lang, Marc; Pw, Manley; Traxler, Peter; Wietfeld, Bernhard; Brüggen, Josef; Buchdunger, Elisabeth; Cozens, Robert; Ferrari, Stefano; Furet, Pascal; Hofmann, Francesco; Martiny-Baron, Georg; Mestan, Juergen; Rösel, Johannes; Sills, Matthew A.; Stover, David R.; Acemoglu, Figan; Boss, Eugen; Emmenegger, R; Lasser, L; Masso, Elvira; Roth, Richard A.; Schlachter, C; Vetterli, W

doi:10.1021/jm9909443

Cited by 223 publications

(177 citation statements)

References 39 publications

Supporting

Mentioning

171

Contrasting

Unclassified

Order By: Relevance

“…Imatinib mesylate was extracted from capsules of Gleevec. Vatalanib was prepared according to the published procedure (11). THRX-165724 was prepared by coupling piperazine to the carboxyl group of SU6668 (12).…”

Section: Methodsmentioning

confidence: 99%

Discovery of a fusion kinase in EOL-1 cells and idiopathic hypereosinophilic syndrome

Griffin

Leung²,

Bruner³

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

189

141

View full text Add to dashboard Cite

Idiopathic hypereosinophilic syndrome (HES) is a myeloproliferative disease of unknown etiology. Recently, it has been reported that imatinib mesylate (Gleevec), an inhibitor of Bcr-Abl kinase useful in the treatment of chronic myeloid leukemia, is also effective in treating HES; however, the molecular target of imatinib in HES is unknown. This report identifies a genetic rearrangement in the eosinophilic cell line EOL-1 that results in the expression of a fusion protein comprising an N-terminal region encoded by a gene of unknown function with the GenBank accession number NM 030917 and a C-terminal region derived from the intracellular domain of the platelet-derived growth factor receptor ␣ (PDGFR␣). The fusion gene was also detected in blood cells from two patients with HES. We propose naming NM 030917 Rhe for Rearranged in hypereosinophilia. Rhe-PDGFR␣ fusions result from an apparent interstitial deletion that links Rhe to exon 12 of PDGFR␣ on chromosome 4q12. The fusion kinase Rhe-PDGFR␣ is constitutively phosphorylated and supports IL-3-independent growth when expressed in BaF3 cells. Proliferation and viability of EOL-1 and BaF3 cells expressing Rhe-PDGFR␣ are ablated by the PDGFR␣ inhibitors imatinib, vatalanib, and THRX-165724.

show abstract

Section: Methodsmentioning

confidence: 99%

Discovery of a fusion kinase in EOL-1 cells and idiopathic hypereosinophilic syndrome

Griffin

Leung²,

Bruner³

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

189

141

View full text Add to dashboard Cite

show abstract

“…The in vitro kinase assays were performed in 96-well plates (30 l) at ambient temperature for 15-45 min using the recombinant glutathione S-transferase-fused kinase domains (4 -100 ng, de- pending on specific activity) prepared as described previously (31,46). [␥ 33 P]ATP was used as phosphate donor and polyGluTyr-(4:1) peptide as acceptor.…”

Section: Methodsmentioning

confidence: 99%

“…Assays were optimized for each kinase using the following ATP concentrations: were calculated by linear regression analysis of the percentage inhibition and are averages of at least three determinations. More details of kinase assays can be found elsewhere (31,46).…”

Section: Methodsmentioning

confidence: 99%

Aee788

Traxler

Allegrini²,

Brandt³

et al. 2004

Cancer Research

Self Cite

297

View full text Add to dashboard Cite

Aberrant epidermal growth factor receptor (EGFR) and ErbB2 expression are associated with advanced disease and poor patient prognosis in many tumor types (breast, lung, ovarian, prostate, glioma, gastric, and squamous carcinoma of head and neck). In addition, a constitutively active EGFR type III deletion mutant has been identified in non-small cell lung cancer, glioblastomas, and breast tumors. Hence, members of the EGFR family are viewed as promising therapeutic targets in the fight against cancer. In a similar vein, vascular endothelial growth factor (VEGF) receptor kinases are also promising targets in terms of an antiangiogenic treatment strategy. AEE788, obtained by optimization of the 7H-pyrrolo[2,3-d]pyrimidine lead scaffold, is a potent combined inhibitor of both epidermal growth factor (EGF) and VEGF receptor tyrosine kinase family members on the isolated enzyme level and in cellular systems. At the enzyme level, AEE788 inhibited EGFR and VEGF receptor tyrosine kinases in the nM range (IC 50 s: EGFR 2 nM, ErbB2 6 nM, KDR 77 nM, and Flt-1 59 nM). In cells, growth factor-induced EGFR and ErbB2 phosphorylation was also efficiently inhibited (IC 50 s: 11 and 220 nM, respectively). AEE788 demonstrated antiproliferative activity against a range of EGFR and ErbB2-overexpressing cell lines (including EGFRvIII-dependent lines) and inhibited the proliferation of epidermal growth factor-and VEGF-stimulated human umbilical vein endothelial cells. These properties, combined with a favorable pharmacokinetic profile, were associated with a potent antitumor activity in a number of animal models of cancer, including tumors that overexpress EGFR and or ErbB2. Oral administration of AEE788 to tumor-bearing mice resulted in high and persistent compound levels in tumor tissue. Moreover, AEE788 efficiently inhibited growth factor-induced EGFR and ErbB2 phosphorylation in tumors for >72 h, a phenomenon correlating with the antitumor efficacy of intermittent treatment schedules. Strikingly, AEE788 also inhibited VEGF-induced angiogenesis in a murine implant model. Antiangiogenic activity was also apparent by measurement of tumor vascular permeability and interstitial leakage space using dynamic contrast enhanced magnetic resonance imaging methodology. Taken together, these data indicate that AEE788 has potential as an anticancer agent targeting deregulated tumor cell proliferation as well as angiogenic parameters. Consequently, AEE788 is currently in Phase I clinical trials in oncology.

show abstract

“…8,9 In finding new β-methoxyacrylate derivatives, we observed that, phthalazines attached to these pharmacophore were not studied. Phthalazin-1(2H)-one derivatives are of considerable interest due to their antidiabetic, 10 antiallergic, 11 vasorelaxant, 12 PDE4 inhibitor, 13 VEGF (vascular endothelial growth factor) receptor tyrosine kinase (for the treatment of cancer), 14 antiasthmatic, 15 and herbicidal 16 activities. A number of established drug molecules like Hydralazine, 17,18 Budralazine, 19,20 Azelastine, 21,22 Ponalrestat, 23 and Zopolrestat, 24 were prepared from the corresponding phthalazinones.…”

Section: Introductionmentioning

confidence: 99%

“…8,9 In finding new β-methoxyacrylate derivatives, we observed that, phthalazines attached to these pharmacophore were not studied. Phthalazin-1(2H)-one derivatives are of considerable interest due to their antidiabetic, 10 antiallergic, 11 vasorelaxant, 12 PDE4 inhibitor, 13 VEGF (vascular endothelial growth factor) receptor tyrosine kinase (for the treatment of cancer), 14 The diverse biological activities of β-methoxyacrylate, phthalazin-1(2H)-one, and isoxazoline pharmacophores envisaged us to plan a new lead compounds that may exhibit wide pharmacological activities. By combining these pharmacophore components in a molecule to give a compact system, we designed and synthesized a series of phthalazin-1(2H)-one derivatives containing β-methoxyacrylate and isoxazoline moieties.…”

mentioning

confidence: 99%

Synthesis, antimicrobial and cytotoxicity studies of some novel modified Strobilurin derivatives

Sridhara¹,

Reddy²,

Keshavayya³

et al. 2011

J. Braz. Chem. Soc.

View full text Add to dashboard Cite

Uma série de novas 3-isoxazolinas substituídas, derivadas do metil-3-metóxi-2-(4-oxo-3,4-diidroftalazin-1-il)prop-2-enoato foram estudadas e sintetizadas a partir do metil-(4-oxo-3,4-diidroftalazin-1-il)acetato, o qual foi preparado a partir do anidrido ftálico. As estruturas dos novos compostos sintetizados foram caracterizadas por dados espectrais e suas atividades antimicrobianas e citotóxicas estudadas. Vários desses compostos mostraram boa atividade antimicrobiana.A series of some new 3-isoxazoline substituted methyl-3-methoxy-2-(4-oxo-3,4-dihydrophthalazin-1-yl)prop-2-enoate derivatives were designed and synthesized from methyl-(4-oxo-3,4-dihydrophthalazin-1-yl)acetate, which in turn was prepared from phthalic anhydride. The structures of synthesized new compounds were characterized by spectral data and studied for their antimicrobial activities and cytotoxicity. Several of these compounds showed good antimicrobial activity.Keywords: phthalazin-1(2H)-one, β-methoxyacrylate, strobilurins, isoxazoline IntroductionNitrogen-containing heterocyclic molecules constitute the largest portion of chemical entities, which are part of many natural products, fine chemicals, and biologically active pharmaceuticals. Strobilurins and their analogues constitute a large group of compounds that represent a new class of plant-protecting agents 1 that meet all the demands that are made nowadays for pesticides. They exhibit efficacy against a broad-spectrum of fungal diseases, possess significant post-infective activity, and have a unique mode of action. 2 Intensive studies aimed at a search for novel biologically active methoxyacrylate fungicides are currently under way by different manufacturers. 3 Studies on the structure of natural methoxyacrylates have made possible to create a novel class of synthetic fungicides with enhanced stability, high activity, and a broad spectrum of action. β-Methoxyacrylate which is a critical and common structural element of strobilurins, fund use in agrochemical agents, 4 antivirals, 5 antimalarials, 6 and fungicides. 7 There has been extensive industrial development of these compounds and their analogues. 8,9 In finding new β-methoxyacrylate derivatives, we observed that, phthalazines attached to these pharmacophore were not studied. Phthalazin-1(2H)-one derivatives are of considerable interest due to their antidiabetic, 10 antiallergic, 11 vasorelaxant, 12 PDE4 inhibitor, 13 VEGF (vascular endothelial growth factor) receptor tyrosine kinase (for the treatment of cancer), 14 The diverse biological activities of β-methoxyacrylate, phthalazin-1(2H)-one, and isoxazoline pharmacophores envisaged us to plan a new lead compounds that may exhibit wide pharmacological activities. By combining these pharmacophore components in a molecule to give a compact system, we designed and synthesized a series of phthalazin-1(2H)-one derivatives containing β-methoxyacrylate and isoxazoline moieties. Figure 1 reveals a framework of these three important biological active pharmacophore component systems.The synth...

show abstract

New Anilinophthalazines as Potent and Orally Well Absorbed Inhibitors of the VEGF Receptor Tyrosine Kinases Useful as Antagonists of Tumor-Driven Angiogenesis

Cited by 223 publications

References 39 publications

Discovery of a fusion kinase in EOL-1 cells and idiopathic hypereosinophilic syndrome

Discovery of a fusion kinase in EOL-1 cells and idiopathic hypereosinophilic syndrome

Aee788

Synthesis, antimicrobial and cytotoxicity studies of some novel modified Strobilurin derivatives

Contact Info

Product

Resources

About