New insights gained for emerging cancer target
Post-translational modification (an addition to a protein after it has been made) is central to cellular signaling processes. Deregulation of these modifications is frequently associated with human pathogenesis, providing opportunities for therapeutic intervention. Ubiquitination is a post-translational modification and comprises a network of proteins dedicated to the ubiquitylation of cellular targets and the subsequent control of numerous cellular functions. Alterations in the ubiquitin system that occur during the initiation and progression of cancer are now being uncovered, and this knowledge is starting to be exploited for both molecular diagnostics and the development of novel strategies to combat cancer.
New research has led to a greater understanding of a related regulatory mechanism known as neddylation. This consists of the covalent attachment of the small protein NEDD8 (the closest relative to ubiquitin) to target proteins, thereby modifying their biochemical properties and protein partners. In contrast to ubiquitination which is known to regulate a myriad of processes in eukaryotic cells, only a limited number of neddylation substrates have been described to date. MLN4924, which is a general inhibitor of neddylation, has been shown to have substantial activity in a broad range of preclinical tumor models, raising the possibility that components of the neddylation pathway might be promising therapeutic targets (Tanaka et al., 2013). Recent publications have shown efficacy of MLN4924 in liver (Lou et al., 2012) and prostate (Wang et al., 2014) cancer cells in support of this hypothesis.
Protein crystallography has come to play an increasingly critical role in the drug discovery process. Key developments have come in the methods for determining protein structures, in particular, X-ray crystallography and automation of screening workflows (facilitated by robots such as TTP Labtech’s mosquito and dragonfly liquid handlers) for protein crystal production. These methods provide the essential structural information on specific protein targets that allows the rational design of novel and improved drug candidates. Last month, the crystal structure of the human COP9 signalosome was published (Lingaraju et al., 2014). This protease comprises eight distinct proteins and is responsible for NEDD8 removal from proteins to modulate their function. The structure reveals the elegant interplay between multiple architectural elements that help detail the complexes mechanism to both sense and signal.
“The availability of the COP9 signalosome crystal structure provides a valuable insight into the regulation of this important protein degradation pathway and highlights how protein crystallography is increasingly able to solve even the most difficult multi-component targets”, commented Dr Paul Thaw, TTP Labtech, “I hope this will lead to the discovery of additional inhibitors of this pathway with enhanced therapeutic potential”.