New Drug Prevents Cancer Cells from Staging Last Stand Unlike many last stands in human history, the last stands arranged by individual cancer cells often resist being overwhelmed, with dire consequences for cancer patients. Cancer cells maintain themselves by coopting autophagy, an energy-harvesting process that is normally used to recycle damaged organelles and proteins. And autophagy is especially important to cancer cells that have been cut off from nutrient pathways, due to the attacks of cancer drugs such as rampamycin (mTOR) inhibitors. Now it appears a coordinated attack may be possible, one that would include a new drug, a small molecule called SBI-0206965 that inhibits autophagy. Such a coordinated attack could effectively overrun cancer before it could muster one last defense, and possibly survive to fight another day. The new drug targets ULK1, an enzyme that initiates autophagy. The drug, which was developed by scientists at Salk Institute and Sanford Burnham Prebys Medical Discovery Institute (SBP), was described June 25 in Molecular Cell, in an article entitled, �Small Molecule Inhibition of the Autophagy Kinase ULK1 and Identification of ULK1 Substrates.� �[We] screened degenerate peptide libraries to deduce the optimal ULK1 substrate motif and discovered 15 phosphorylation sites in core autophagy proteins that were verified as in vivo ULK1 targets,� wrote the authors. �We utilized these ULK1 substrates to perform a cell-based screen to identify and characterize a potent ULK1 small molecule inhibitor.� According to this study, SBI-0206965 proved to be a highly selective ULK1 kinase inhibitor in vitro, and it suppressed ULK1-mediated phosphorylation events in cells, regulating autophagy and cell survival. In addition, SBI-0206965 combined with starvation or mTOR inhibition leads to ULK1 degradation. Essentially, SBI-0206965 synergizes with mTOR inhibition to induce cell death. "The finding opens the door to a new way to attack cancer," said Reuben Shaw, a senior author of the paper, professor in the Molecular and Cell Biology Laboratory at the Salk Institute and a Howard Hughes Medical Institute Early Career Scientist. "The inhibitor will probably find the greatest utility in combination with targeted therapies." "The key to success for this project came when we combined Reuben's deep understanding of the fundamental biology of autophagy with our chemical expertise," says Cosford. "This allowed us to find a drug that targeted ULK1 not just in a test tube but also in tumor cells. Another challenge was finding molecules that selectively targeted the ULK1 enzyme without affecting healthy cells. Our work provides the basis for a novel drug that will treat resistant cancer by cutting off a main tumor cell survival process."