px-478 and 3-(5--hydroxymethyl-2--furyl)-1-benzylindazole

Hypoxia-inducible factor (HIF) is a heterodimeric transcription factor consisting of α and β subunits that regulates the expression of angiogenic factors, including VEGF, which are involved in angiogenesis, invasion/metastasis, glucose uptake and cell survival during cancer development.. This review summarizes the information about patented HIF inhibitors over the last 7 years (2004 - 2010). The reader will gain an outline of the structure and biological activity of recently developed HIF inhibitors.. Inhibition of HIF is an attractive therapeutic target for tumor angiogenesis and, until now, various HIF inhibitors have been discovered and evaluated. It is expected that development of more potent and selective HIF inhibitors will provide an effective treatment of cancer and other HIF-related diseases, including inflammation and cardiovascular disorder. As VEGF plays an important role in angiogenesis during tumor growth and ischemic diseases, the inhibition of VEGF-induced HIF is an attractive approach for the suppression of hypoxia-mediated pathological angiogenesis. HIF inhibitors may not only have cytostatic antitumor effects with fewer side effects, but also synergetic effects combined with radiotherapy.

Topics: Animals; Antineoplastic Agents; Disulfides; Estradiol; Furans; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Imidazoles; Indazoles; Mustard Compounds; Patents as Topic; Phenylpropionates; Piperazines

Most solid tumors develop regions of hypoxia as they grow and outstrip their blood supply. In order to survive in the stressful hypoxic environment, tumor cells have developed a coordinated set of responses orchestrating their adaptation to hypoxia. The outcomes of the cellular responses to hypoxia are aggressive disease, resistance to therapy, and decreased patient survival. A critical mediator of the hypoxic response is the transcription factor hypoxia-inducible factor 1 (HIF-1) that upregulates expression of proteins that promote angiogenesis, anaerobic metabolism, and many other survival pathways. Regulation of HIF-1alpha, a component of the HIF-1 heterodimer, occurs at multiple levels including translation, degradation, and transcriptional activation, and serves as a testimony to the central role of HIF-1. Studies demonstrating the importance of HIF-1alpha expression for tumor survival have made HIF-1alpha an attractive target for cancer therapy. The growing l.ist of pharmacological inhibitors of HIF-1 and their varied targets mirrors the complex molecular mechanisms controlling HIF-1. In this chapter, we summarize recent findings regarding the regulation of HIF-1alpha and the progress made in identifying new therapeutic agents that inhibit HIF-1alpha.

Topics: Animals; Cell Hypoxia; Histone Deacetylase Inhibitors; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Indazoles; Mustard Compounds; Neoplasms; Phenylpropionates; Proto-Oncogene Proteins c-myc; Tumor Suppressor Protein p53

Topics: Animals; Antineoplastic Agents; Clinical Trials, Phase I as Topic; DNA-Binding Proteins; Drugs, Investigational; Humans; Hypoxia-Inducible Factor 1; Hypoxia-Inducible Factor 1, alpha Subunit; Indazoles; Mustard Compounds; Neoplasms; Neovascularization, Pathologic; Nuclear Proteins; Phenylpropionates; Topotecan; Transcription Factors; Transplantation, Heterologous