Pharmacological Inhibition of ULK1 Kinase Blocks Mammalian Target of Rapamycin (mTOR)-dependent Autophagy

Autophagy is a cell-protective and degradative process that recycles damaged and long-lived cellular components. Cancer cells are thought to take advantage of autophagy to help them to cope with the stress of tumorigenesis; thus targeting autophagy is an attractive therapeutic approach. However, there are currently no specific inhibitors of autophagy. ULK1, a serine/threonine protein kinase, is essential for the initial stages of autophagy, and here we report that two compounds, MRT67307 and MRT68921, potently inhibit ULK1 and ULK2 in vitro and block autophagy in cells. Using a drug-resistant ULK1 mutant, we show that the autophagy-inhibiting capacity of the compounds is specifically through ULK1. ULK1 inhibition results in accumulation of stalled early autophagosomal structures, indicating a role for ULK1 in the maturation of autophagosomes as well as initiation.     

Ligand-based virtual screening using binary kernel discrimination

This paper discusses the use of a machine-learning technique called binary kernel discrimination (BKD) for virtual screening in drug- and pesticide-discovery programmes. BKD is compared with several other ligand-based tools for virtual screening in databases of 2D structures represented by fragment bit-strings, and is shown to provide an effective, and reasonably efficient, way of prioritising compounds for biological screening.