piperidines and vatalanib

Functional blood vasculature is essential for tumor progression. The main signalization pathways that play a key role in the survival and growth of tumor vessels originate from the VEGF-, PDGF- and FGF tyrosine kinase receptors. In the past decade, significant results have been published on receptor tyrosine kinase inhibitors (RTKIs). In this paper, the mechanisms of action and the results so far available of experimental and clinical studies on multi-target antiangiogenic TKIs are discussed. On the one hand, notable achievements have been made recently and these drugs are already used in clinical practice in some patient populations. On the other hand, the optimal combination and dosage of these drugs, selection of the apropriate biomarker and better understanding of the conflicting role of PDGFR and FGFR signaling in angiogenesis remain future challenges.

Topics: Angiogenesis Inhibitors; Animals; Axitinib; Benzenesulfonates; Humans; Imidazoles; Indazoles; Indoles; Neoplasms; Neovascularization, Pathologic; Niacinamide; Oligonucleotides; Phenylurea Compounds; Phthalazines; Piperidines; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Pyridines; Pyrimidines; Pyrroles; Quinazolines; Receptor Protein-Tyrosine Kinases; Receptors, Fibroblast Growth Factor; Receptors, Platelet-Derived Growth Factor; Receptors, Vascular Endothelial Growth Factor; Signal Transduction; Sorafenib; Sulfonamides; Sunitinib

Angiogenesis is essential for tumor growth and metastasis. The main regulators of the process are the signaling cascades of VEGF-, PDGF- and FGF receptors. Inhibition of these pathways holds potential therapeutic benefit not only for cancer patients, but also for the treatment of other diseases. This paper summarizes the experimental and clinical results of studies available so far on the multi-target tyrosine kinase inhibitor nintedanib (BIBF 1120). According to these studies, nintedanib effectively inhibits VEGFR-, PDGFR- and FGFR signalization and thus the proliferation and survival of cell types which highly express these receptors (i.e. endothelial and smooth muscle cells and pericytes). In vitro studies and in vivo xenograft experiments have provided promising results. In the clinical setting, BIBF 1120 seems to be effective and well tolerated in various tumor types, such as lung, prostate, colorectal and hepatocellular carcinoma, as well as in gynecological tumors. The main adverse events are gastrointestinal toxicities and the reversible elevation of liver enzyme levels. Nintedanib might also be combined with paclitaxel, carboplatin, pemetrexed and docetaxel. There are several ongoing clinical trials testing the efficacy of BIBF 1120.

Topics: Animals; Antineoplastic Agents; Axitinib; Benzenesulfonates; Carcinoma, Hepatocellular; Clinical Trials as Topic; Colorectal Neoplasms; Digestive System; Enzyme Inhibitors; Female; Genital Neoplasms, Female; Humans; Imidazoles; Indazoles; Indoles; Liver Neoplasms; Lung Neoplasms; Male; Neoplasms; Niacinamide; Oligonucleotides; Phenylurea Compounds; Phthalazines; Piperidines; Prostatic Neoplasms; Protein-Tyrosine Kinases; Pyridines; Pyrimidines; Quinazolines; Receptors, Fibroblast Growth Factor; Receptors, Platelet-Derived Growth Factor; Receptors, Vascular Endothelial Growth Factor; Signal Transduction; Sorafenib; Sulfonamides; Xenograft Model Antitumor Assays

Approximately 90 % of gastrointestinal tumors (GISTs) harbor an activating mutation in KIT or PDGFR alpha oncogene known to confer imatinib sensitivity. Imatinib is a tyrosine kinase inhibitor of KIT and PDGFRs that yields a 6-months progression-free survival (PFS) rate of 80 % in patients with advanced GISTs. Several studies have shown that response to imatinib in GIST patients mainly depends on the mutational status of KIT or PDGFR alpha. Moreover, most if not all patients treated with imatinib for advanced GIST will secondarily develop progressive disease under treatment. In the majority of cases, such progressions are the result of acquired resistance due to occurrence of secondary C-KIT mutations; especially for GIST with primary exon 11 mutations. Sunitinib is another approved drug and an inhibitor of multiple tyrosine kinases including KIT, PDGFR alpha as well as PDGFR beta and VEGFRs which are associated with angiogenesis. Sunitinib, in phase II and III trials was associated with durable clinical benefit in nearly 25 % of patients with advanced GIST resistant/intolerant to imatinib. Clearly, a better knowledge of the molecular mechanisms underlying the resistance to imatinib as well as the development of a new class of broad-spectrum tyrosine kinase inhibitors may allow in the near future new individualized therapeutic strategies for GISTs patients.

Topics: Antineoplastic Agents; Benzamides; Benzenesulfonates; Disease Progression; Drug Resistance, Neoplasm; Gastrointestinal Stromal Tumors; Humans; Imatinib Mesylate; Indoles; Mutation; Neoplasm Proteins; Niacinamide; Oligonucleotides; Phenylurea Compounds; Phthalazines; Piperazines; Piperidines; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-kit; Pyridines; Pyrimidines; Pyrroles; Receptor, Platelet-Derived Growth Factor alpha; Sorafenib; Staurosporine; Sunitinib; Thiazoles

Angiogenesis does not initiate malignancy but promotes tumor progression and metastasis. Inhibiting angiogenesis is now a validated strategy for treatment of cancer. In order to do it, different ways are under investigation from cellular therapy to oral agents. Nowadays targeting angiogenesis with small molecules mainly concern inhibition of the VEGF receptors tyrosine kinase activity. Five molecules are currently in phase III trials and two of them (sunitinib and sorafenib) have been approved by the FDA for the treatment of advanced renal cancer. Despite those encouraging results, numerous points remain unclear. The toxicity profile seems to be favourable but long term effects could be problematic. Indeed, clinical trials have pointed out the role of VEGF pathway in the maintenance of numerous physiological functions. Moreover, none of the agents are specifically anti-angiogenic and the respective parts of the "off target" effects are difficult to evaluate. Simple and reliable surrogate markers of toxicity and efficacy are still lacking.

Topics: Administration, Oral; Angiogenesis Inhibitors; Animals; Asthenia; Axitinib; Benzenesulfonates; Humans; Hypertension; Imidazoles; Indazoles; Indoles; Neoplasms; Neovascularization, Pathologic; Niacinamide; Phenylurea Compounds; Phthalazines; Piperidines; Proteinuria; Pyridines; Pyrroles; Quinazolines; Receptors, Vascular Endothelial Growth Factor; Sorafenib; Sunitinib; Vascular Endothelial Growth Factor A

Non-small cell lung cancer (NSCLC) remains the leading cause of cancer-related mortality in the United States. Therapeutic agents that target the underlying biology of this disease are necessary to improve outcomes. Angiogenesis plays a central role in NSCLC tumor growth and metastases. The vascular endothelial growth factor pathway (VEGF) as a therapeutic target was recently validated in NSCLC. Since then, a multitude of early phase clinical trials that incorporate the use of angiogenesis inhibitors, either as single agents or in combination with cytotoxic chemotherapy, have been conducted in advanced, refractory NSCLC. This article reviews these clinical trials with attention to toxicity, efficacy, and direction of further study. The data from these trials suggest that optimal use of anti-angiogenic agents in NSCLC is more likely in combination with standard cytotoxic agents, however the most effective combination with the least toxicity is yet to be determined.

Topics: Angiogenesis Inhibitors; Antineoplastic Agents; Benzenesulfonates; Carcinoma, Non-Small-Cell Lung; Clinical Trials as Topic; Humans; Indoles; Neovascularization, Pathologic; Niacinamide; Oligonucleotides; Phenylurea Compounds; Phthalazines; Piperidines; Protein-Tyrosine Kinases; Pyridines; Pyrroles; Quinazolines; Receptors, Vascular Endothelial Growth Factor; Sorafenib; Sunitinib; Treatment Outcome

Lung cancer is the most common cause of cancer death worldwide, with most patients dying with metastatic disease. The prognosis for the majority of patients remains poor. It is evident that advances in the treatment of this and other tumor types will require new approaches, and recent research has focused on molecular-targeted therapies. A key therapeutic strategy is inhibition of specific processes essential for tumor vascular development (a concept known to be beneficial in colorectal cancer) and a range of such antiangiogenic agents are currently in development. The most promising of these target the proangiogenic vascular endothelial growth factor (VEGF), either by preventing VEGF-receptor binding or inhibiting downstream receptor signaling. However, other more direct approaches against tumor vasculature are also in development. Since antiangiogenic agents often exert an indirect, cytostatic effect, many are being evaluated in combination with conventional chemotherapies in order to optimize the anticancer effects of both strategies. Additionally, the combination of several antiangiogenic agents is also being explored. This has become possible given the large number of agents currently available. As part of this evaluation process, the assessment of surrogate markers of target inhibition and treatment effect is ongoing in the hope of identifying reliable surrogate markers to aid the development of this new generation of anticancer agents.

Topics: Angiogenesis Inhibitors; Benzenesulfonates; Biomarkers, Tumor; Carcinoma, Non-Small-Cell Lung; Humans; Lung; Lung Neoplasms; Neovascularization, Pathologic; Niacinamide; Phenylurea Compounds; Phthalazines; Piperidines; Prognosis; Pyridines; Quinazolines; Randomized Controlled Trials as Topic; Sorafenib

A number of therapeutic agents have been developed which have anti-angiogenic potential. Here we present the most recent data from clinical trials with some of the promising inhibitors of angiogenesis.. Agents that target the vascular endothelial growth factor signaling pathway are the furthest along in clinical development. The last year has brought US Food and Drug Administration approval of bevacizumab (Avastin), a recombinant humanized anti-vascular endothelial growth factor monoclonal antibody. Bevacizumab has demonstrated a survival advantage in combination with chemotherapy for patients with metastatic colorectal cancer. Other agents with early promising results include PTK787/ZK 222584 (Vatalanib), ZD6474, and BAY 43-9006 (Sorafenib).. Angiogenesis inhibitors show promise, but evaluation for optimal efficacy has been a problem, given that the mechanisms of action of these agents differ from conventional cytotoxic agents and surrogate markers for inhibition of angiogenesis are not available.

Topics: Angiogenesis Inhibitors; Animals; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Benzenesulfonates; Bevacizumab; Colorectal Neoplasms; Humans; Neoplasms; Neovascularization, Pathologic; Niacinamide; Phenylurea Compounds; Phthalazines; Piperidines; Pyridines; Quinazolines; Randomized Controlled Trials as Topic; Signal Transduction; Sorafenib; Vascular Endothelial Growth Factor A

Recent progress in molecular biology and cancer biology has revealed that many molecules, which are heavily involved in the un-limited growth, anti-apoptotic effects and invasion of tumors, would be targets of cancer therapy. Part of the drugs which inhibit these molecules have shown clinical response as well as clinical benefits. In this review article, the summary of mechanism based drug screening for cancer as well as recent status of new molecular target drugs for cancer, are described.

Topics: Angiogenesis Inhibitors; Animals; Antineoplastic Agents; Benzamides; Boronic Acids; Bortezomib; Drug Delivery Systems; Drug Screening Assays, Antitumor; Gefitinib; Heat-Shock Proteins; Humans; Imatinib Mesylate; Indoles; Lactones; Mice; Neoplasms; Phthalazines; Piperazines; Piperidines; Pyrazines; Pyridines; Pyrimidines; Pyrroles; Quinazolines; Sunitinib

The inhibitors of VEGF-mediated signaling continue to wind their way through extensive preclinical and clinical development paths. Whereas the first phase III trial did not meet its endpoints, one hopes that the others will. As we learn more about the VEGF pathways in the laboratory and the clinic, we can interpret with greater certainty what role these drugs or their successors will have in the treatment of human cancers.

Topics: Angiogenesis Inhibitors; Animals; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Bevacizumab; Clinical Trials as Topic; Colorectal Neoplasms; Drug Design; Drug Screening Assays, Antitumor; Endothelial Growth Factors; Enzyme Inhibitors; Humans; Indoles; Intercellular Signaling Peptides and Proteins; Lymphokines; Neoplasm Proteins; Neoplasms; Neovascularization, Pathologic; Phthalazines; Piperidines; Pyridines; Pyrroles; Quinazolines; Recombinant Proteins; RNA, Catalytic; Treatment Failure; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-1; Vascular Endothelial Growth Factor Receptor-2; Vascular Endothelial Growth Factors

Topics: Benzamides; Benzimidazoles; Cytochrome P-450 CYP2C8; Cytochrome P-450 CYP2C8 Inhibitors; Cytochrome P-450 CYP3A; Cytochrome P-450 CYP3A Inhibitors; Drug Interactions; Humans; Indoles; Inhibitory Concentration 50; Microsomes, Liver; Phthalazines; Piperidines; Pyridines; Pyridones; Pyrimidinones; Quinolones; Staurosporine; Thiazoles

Extensive oncologic experience argues that the most efficacious applications of antiangiogenic agents rely upon a combination with cytotoxic drugs. Yet there remains a lack of clarity about how to optimize scheduling for such drug combinations. Prudent antiangiogenic therapy might transiently normalize blood vessels to improve tumor oxygenation and drug exposure. Using [(15)O]H2O positron emission tomography imaging in a preclinical mouse model of non-small cell lung cancer, we observed that short-term treatment with the vascular endothelial growth factor receptor/platelet-derived growth factor receptor inhibitor PTK787 licensed a transient window of improved tumor blood flow. The improvement observed was associated with a reduced leakiness from tumor vessels, consistent with induction of a vascular normalization process. Initiation of a cytotoxic treatment in this window of tumor vessel normalization resulted in increased efficacy, as illustrated by improved outcomes of erlotinib administration after initial PTK787 treatment. Notably, intermittent PTK787 treatment also facilitated long-term tumor regression. In summary, our findings offer strong evidence that short-term antiangiogenic therapy can promote a transient vessel normalization process that improves the delivery and efficacy of a targeted cytotoxic drug.

Topics: Angiogenesis Inhibitors; Animals; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Drug Synergism; Erlotinib Hydrochloride; Humans; Lung Neoplasms; Male; Mass Spectrometry; Mice; Mice, Nude; Multimodal Imaging; Phthalazines; Piperidines; Positron-Emission Tomography; Protein Kinase Inhibitors; Pyridines; Quinazolines; Receptors, Platelet-Derived Growth Factor; Receptors, Vascular Endothelial Growth Factor; Xenograft Model Antitumor Assays

Fibroblast growth factor receptor 3 (FGFR3) is up-regulated as a result of the t(4;14)(p16;q32) translocation that occurs in up to 20% of multiple myeloma (MM) patients. Recent studies have demonstrated that up-regulation of FGFR3 promotes cell survival, growth and drug resistance in malignant plasma cells, both in vitro and in vivo. Therefore, inhibition of FGFR3 signalling is potential target for the chemotherapeutic intervention in t(4;14) MM.. Small molecule receptor tyrosine kinase inhibitors (PD173074, sunitinib (SU-11248), vandetanib (ZD6474) and vatalanib (PTK-787)) with varying degrees of inhibitory activity and selectivity against FGFR, were assessed in Ba/f3 cells expressing ZNF198-FGFR1 and MM cell lines. Cell viability, FGFR3 and ZNF198-FGFR1 phosphorylation and apoptosis were evaluated by growth inhibition assays, immunoblotting and fluorescence-activated cell sorting analysis, respectively. An in vivo study was performed with sunitinib in t(4;14)-positive and t(4;14)-negative human MM tumour xenograft models.. PD173074 and sunitinib differentially inhibited the growth of Ba/f3 cells expressing ZNF198-FGFR1 (GI(50)=10 nM and 730 nM, versus GI(50) >1 μM and 2.7 μM for parental cells; p<0.0001) and t(4;14) positive MM cell lines (GI(50)=4-10 μM and 1-3 μM, versus GI(50)=14-15 μM and 4-5 μM for t(4;14) negative MM cells; p≤0.002). In addition, both PD173074 and sunitinib inhibited the activation of FGFR3 in t(4;14)-positive MM cells. PD173074 and sunitinib induced an apoptotic response in a concentration and time-dependent manner in a t(4;14)-positive (PD174073 and sunitinib) but not a t(4;14)-negative MM cell line (sunitinib only); however, in in vivo tumours derived from the same cell lines, sunitinib was only active in the t(4;14)-negative model.. These data demonstrate that PD173074 and sunitinib are inhibitors of FGFR3 in MM cell lines, and that sunitinib has in vivo activity in a human MM tumour xenograft model. However, caution should be exercised in using the t(4;14) translocation as a predictive biomarker for patient selection in clinical trials with sunitinib.

Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Drug Evaluation, Preclinical; Humans; Indoles; Mice; Mice, Inbred BALB C; Mice, Nude; Multiple Myeloma; Phthalazines; Piperidines; Protein Kinase Inhibitors; Pyridines; Pyrimidines; Pyrroles; Quinazolines; Receptor Protein-Tyrosine Kinases; Sunitinib; Xenograft Model Antitumor Assays

We have developed a series of novel potent 1-(2-(pyridin-4-yl)ethyl)-1H-azole-5-carboxamides active against kinases VEGFR-2 and -1. Both specific and dual ATP-competitive inhibitors of VEGFR-2 were identified. Kinase selectivity could be controlled by varying the 5-carboxamide substituent at the azole ring. The most specific molecules displayed >10-fold selectivity for VEGFR-2 over VEGFR-1. Compound activities in vitro and in cell-based assays (IC(50)<100 nM) were similar to those of reported clinical and development candidates, including PTK787 (Vatalanib(trade)) and ZD6474 (Vandetanib(trade mark)). High permeability of active compounds across the Caco-2 cell monolayer (>40 x 10(-5)cm/min) is indicative of their potential for intestinal absorption upon oral administration.

Topics: Adenosine Triphosphate; Amides; Azoles; Binding, Competitive; Caco-2 Cells; Cell Line, Tumor; Chemistry, Pharmaceutical; Drug Screening Assays, Antitumor; Humans; Inhibitory Concentration 50; Models, Chemical; Phthalazines; Piperidines; Protein Kinase Inhibitors; Pyridines; Quinazolines; Vascular Endothelial Growth Factor Receptor-1; Vascular Endothelial Growth Factor Receptor-2