Our new paper describes drug with potential for new anticancer strategy

I just wanted to use this post to give a little shameless promotion to the work published by the Shaw and Cosford labs (that includes me!) last week. I've put links below to the press it received as well as to the article itself.

The work we published sheds more light on the autophagy process and its relevance to cancer therapy. Specifically, our labs have helped to advance the understanding of a hot new target, ULK1, that is crucial to autophagy. We show in the paper that induction of autophagy by nutrient limitation (similar to the tumor microenvironment of a cancer) or by an mTOR inhibitor combined with inhibition of ULK1 by SBI-0206965 causes cell death. Basically what's happening is we're activating a pathway and preventing it from proceeding further downstream, and the response by the cell is death.

Other labs have very recently released their findings regarding their own ULK1 inhibitors. However, the key difference that sets our compound apart is its selectivity. It turns out our compound, "6965", is amazingly selective. Anyone who's been involved in the development of kinase inhibitors knows that kinase selectivity can be difficult to achieve. The reason being that most small molecules are ATP competitive, and therefore bind to the ATP binding site, a well-conserved region of the enzyme. One example of a highly selective drug used in the clinic to treat breast cancer is the tyrosine kinase inhibitor lapatinib, which is also ATP competitive.

When designing a drug, you generally want that compound to be very specific for the molecular target; whether it be a receptor, kinase, or some other biomolecular target. Off-target effects can often give rise to toxicity from a clinical perspective.

Selectivity is perhaps even more important for biologists using a tool compound to study a biological pathway. Any off-target interactions can cause ripple effects on a number of closely related pathways and even feed back into the pathway the biologist is studying, making analysis very difficult or impossible.

We've synthesized and tested a substantial library of compounds so far, so more publications will follow to detail our discoveries in this developing, but very important field of chemical biology. So stay tuned!

Salk press release
UT San Diego article
Genetic Engineering & Biotechnology News
Molecular Cell article