Allosteric Inhibitors Slow Cancer Growth and Block Angiogenesis

Cancer researchers have demonstrated the potential benefits of a chemotherapeutic approach that targets the class of proteins called RAF (rapidly accelerated fibrosarcoma) kinases, which regulate cell proliferation and survival and are often overly active in tumor cells.

Investigators at the University of California, San Diego (USA) worked with a family of drugs known as allosteric inhibitors. These drugs prevent enzymes from functioning by inducing changes of shape rather than by competing for binding to the enzyme’s active site. A major benefit of this approach is that the cancer cells are much less likely to develop resistance to an allosteric inhibitor.

In the current study, which was published in the November 13, 2011, online issue of the journal Nature Medicine, the investigators tested the drug KG5, which targets RAF in proliferating cells, but ignores normal or resting cells.

They reported that morphological changes in tumor cell RAF caused by KG5 prevented the enzyme from associating with the mitotic apparatus to direct cell division, resulting in cell cycle arrest leading to apoptosis. The drug likewise interfered with blood vessel proliferation (angiogenesis).

“It is an unusual discovery, one that really challenges current dogma,” said senior author Dr. David A. Cheresh, professor of pathology at the University of California, San Diego. “Before this drug was designed, we had no idea RAF could promote tumor cell cycle progression. This may be only one example of how, by designing drugs that avoid the active site of an enzyme, we can identify new and unexpected ways to disrupt the growth of tumors. In essence, we are attacking an important enzyme in a whole new way and thereby discovering new things this enzyme was intended for.”

New allosteric inhibitors that target RAF are being developed by the biotech start-up company Amitech Therapeutic Solutions (San Diego, CA, USA).

Related Links:
University of California, San Diego
Amitech Therapeutic Solutions