Hypoxia‐inducible factor‐1 (HIF‐1) inhibitors from the last decade (2007 to 2016): A “structure–activity relationship” perspective

Abstract

Tumor hypoxia is a common feature in most solid tumors and is associated with overexpression of the hypoxia response pathway. Overexpression of the hypoxia-inducible factor (HIF-1) protein leads to angiogenesis, metastasis, apoptosis resistance, and many other pro-tumorigenic responses in cancer development. HIF-1 is a promising target in cancer drug development to increase the patient's response to chemotherapy and radiotherapy as well as the survival rate of cancer patients. Since up to 1% of genes are hypoxia-sensitive, a target-specific HIF-1 inhibitor may be a better clinical candidate in cancer drug discovery. Though no HIF-1 inhibitor is clinically available to date, a lot of effort has been applied during the last decade in search of potent HIF-1 inhibitors. In this review, we will summarize the structure-activity relationship of ten different chemotypes reported to be HIF-1 inhibitors in the last decade (2007-2016), their mechanisms of action for HIF-1 inhibition, progress in the way of target-specific inhibitors, and problems associated with current inhibitors. It is anticipated that the results of these research on the medicinal chemistry of HIF-1 inhibitors will provide decent information in the design and development of future inhibitors.

Physiological and Biological Responses to Short-Term Intermittent Hypobaric Hypoxia Exposure: From Sports and Mountain Medicine to New Biomedical Applications

“…The molecular mechanisms involved in the response to hypoxia at the cellular level are relatively well understood (Fábián et al, 2016 ; Bhattarai et al, 2017 ; Koyasu et al, 2017 ). However, the complexity of the interactions between the divergent signaling pathways and the time frame of the various processes on different tissues and organs, together with the significant individual variability in humans' susceptibility to hypoxia (Rathat et al, 1992 ), pose formidable challenges to researching the potential benefits of regular programs involving exposure to real or simulated altitudes.…”

“…In addition to its erythropoietic role, HIF-1 is the main mediator of angiogenesis in response to hypoxic conditions (Rey and Semenza, 2010 ) and has been considered a potential therapeutic target in many diseases. Two different strategies have been applied: HIF-1 upregulation for ischemic diseases (Li et al, 2014 ) and HIF-1 inhibition for cancer and endometriosis (Zhou et al, 2012 ; Bhattarai et al, 2017 ). Multiple angiogenic factors have been tested in the past; however, therapies that use only one proangiogenic agent to elicit angiogenesis were shown to be insufficient (Hirota and Semenza, 2006 ).…”

Quantitative MS‐Based Proteomics: Comparing the MCF‐7 Cellular Response to Hypoxia and a 2‐Oxoglutarate Analogue

“…Hypoxic tumour cells have been found to have increased metastatic potential and resistance to radiotherapy and chemotherapy . An improved characterisation of gene regulation in response to hypoxia is of interest to further understand the fundamental biology of the hypoxic response, which in turn might help to inform the development of drugs aimed at suppressing or enhancing levels of HIF …”

<p>Down-Regulation of Hypoxia-Inducible Factor-1α and Downstream Glucose Transporter Protein-1 Gene by β-elemene Enhancing the Radiosensitivity of Lung Adenocarcinoma Transplanted Tumor</p>

“…HIF-1α may be an important sign of rapid tumor proliferation, invasion and deterioration. 11 Therefore, reducing the expression of HIF-1α has become a major focus of current non-small cell lung cancer (NSCLC) treatment research.…”