Wells uses small molecules to trigger cell death

Research directed by senior author James Wells, PhD, chair of the Department of Pharmaceutical Chemistry, UCSF School of Pharmacy, has opened the door to a new way of studying and better understanding the processes of cell death (apoptosis), blood clotting, and other biochemical pathways. Insights could lead to the development of novel therapeutics for diseases such as cancers that are characterized by uncontrolled cell growth.

Wells and his UCSF team used high throughput screening to find small molecules that could activate the inactive precursors of proteases, called proenzymes, that are involved in apoptosis. A small molecule, named compound 1541, robustly activated procaspase-3 and procaspase-6, the precursors to the apoptosis-inducing "executioner" proteases caspases-3 and -6.

Nearly all of the body's inactive proenzymes are stored in the body and tightly regulated. These study results, which were published in the November 6, 2009 issue of Science, showed that it is possible to bypass the body's normal regulatory methods that control the activation of proenymes involved in apoptosis and induce "non-natural" activation in cultured cancer cell lines in the laboratory.

First author of the study is postdoctoral scholar Dennis W. Wolan, PhD, who led the project in Wells' laboratory. Other co-authors are PhD Chemistry and Chemical Biology graduate students Julie Zorn and Daniel Gray.

Research paper

Small-Molecule Activators of a Proenzyme, Science, November 6, 2009


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