HIF-1 Inhibitors

Once solid tumors have grown to a certain size, a lack of oxygen (hypoxia) often suppresses their further growth. Unfortunately, many tumors adapt to this situation through the activation of HIF-1 (hypoxia-inducible factor 1), a transcription factor that senses the low oxygen concentration and activates a series of genes which helps the tumor survive these conditions.

For example, there is evidence that activation of HIF-1 is able to alter the metabolism of tumor cells to use less oxygen. Furthermore, a number of other changes are linked to the activation of HIF-1, including increased breathing and dilation of blood vessels to increase oxygen supply and even the growth of new blood vessels into the tumor from the surrounding tissue (a process known as angiogenesis).

Lead Discovery

We are working to develop a drug candidate for clinical development that acts through inhibiting HIF-1. To date, we have identified lead compounds that block the interaction between HIF-1 alpha and its co-activator p300. Subsequently, in in vitro settings we demonstrated that these compounds are able to block the activation of genes involved in tumor survival, such as VEGF (vascular endothelial growth factor), which plays a pivotal role in angiogenesis.

Two lead compounds will be tested in vivo in a preclinical model of metastatic colon cancer to evaluate their potential antiangiogenic and antitumor effect.

Lead Optimization/Preclinical Studies

We are conducting a second round of preliminary screening, using chemical libraries supplied by NCI and other lead discovery chemical compound suppliers, to identify new lead compounds that will provide a greater chemical diversity for lead optimization.