Open AccessDevelopment of HIF‐1 inhibitors for cancer therapy
Author(s) -
Onnis Barbara,
Rapisarda Annamaria,
Melillo Giovanni
Publication year - 2009
Publication title -
journal of cellular and molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.44
H-Index - 130
eISSN - 1582-4934
pISSN - 1582-1838
DOI - 10.1111/j.1582-4934.2009.00876.x
Subject(s) - clinical trial , medicine , hypoxia (environmental) , drug development , bioinformatics , cancer research , pharmacodynamics , hypoxia inducible factors , cancer , oncology , pharmacology , biology , drug , pharmacokinetics , chemistry , gene , biochemistry , organic chemistry , oxygen
• Introduction • Mechanisms of action of action of HIF‐1 inhibitors ‐ Inhibitors of HIF‐1α mRNA expression ‐ Inhibitors of HIF‐1α protein translation ‐ Inhibitors that affect HIF‐1α degradation pathway ‐ Inhibitors of HIF‐1 binding to DNA ‐ Inhibitors of HIF‐1α transcriptional activity• ConclusionsIntratumour hypoxia has long been considered a driving force of tumour progression and a negative prognostic factor in human cancers. The discovery of hypoxia inducible factors (HIFs), which mediate transcriptional responses to changes in oxygen levels, has renewed enthusiasm for the discovery and development of targeted therapies exploiting the hypoxic tumour microenvironment. In spite of an ever increasing number of putative small molecule inhibitors of HIF, only few progress through pre‐clinical and early clinical development. In this review, we will focus primarily on: (1) HIF inhibitors that have been more recently described and (2) small molecules targeting HIF that are being tested in early clinical trials or that are already approved for use in patients. A rigorous ‘validation’ of HIF targeted therapies in relevant pre‐clinical models and eventually in pharmacodynamic‐based early clinical trials is essential for ‘credentialing’ HIF‐1 as a legitimate target that can be pharmacologically modulated in cancer patients.