Selective Protease Substrates
Proteases, which catalyze the hydrolysis of amide bonds in peptides and proteins, play essential roles in most biological processes and are very important therapeutic and diagnostic targets for a multitude of diseases, including cancer. Efficient and systematic combinatorial tools will be developed to determine the substrate specificity profiles of proteases involved in prostate cancer. Generation of completely selective substrates for prostate cancer proteases will aid in designing more selective diagnostic tools in addition to serving as a basis for protease inhibitor design.
Substrate-competitive Kinase Inhibitors
Protein Tyrosine Kinases (PTKs) are a major contributor to oncogenesis. Over the past decade, much attention has been focused on the development of ATP-competitive inhibitors from both academia and the pharmaceutical industry. Methodology for the generation of substrate-mimetic inhibitors of PTKs will be developed using novel fragment-based high throughput screening methods. Inhibitors that bind in the substrate pocket of a target kinase could help positively address potential issues with modern ATP-competitive inhibitor development, namely selectivity and susceptibility to resistance.
Peptidomimetics for Disruption of Protein-Protein Interactions
Utilizing a novel oligomeric structure, peptidomimetics that adopt helical conformations (foldamers) will be synthesized and evaluated for the targeted disruption of protein-protein interactions involved in oncogenesis.
Matthew B. Soellner, Katherine A. Rawls, Christoph Grundner, Tom Alber, and Ronald T. Raines. Fragment-based substrate activity screening method for the identification of potent inhibitors of the Mycobacterium tuberculosis phosphatase PtpB. J. Am. Chem. Soc. 2007 129 9613-9615. PubMed
Annie Tam, Ulrich Arnold, Matthew B. Soellner, and Ronald T. Raines. Protein prosthesis: 1,5-Disubstituted-[1,2,3]-triazoles as cis peptide bond mimics. J. Am. Chem. Soc. 2007 129 12670-12671. PubMed
Maniere, Molly E. Moore, Matthew B. Soellner, Pearl Tsang, and Carol A. Caperelli. Human glycinamide ribonucleotide transformylase: active site mutants as mechanistic probes Biochemistry 2007 46 146-153. PubMed
Matthew B. Soellner, Annie Tam, and Ronald T. Raines. Staudinger ligation of peptides at non-glycyl residues J. Org. Chem. 2006 71 9824-9830. PubMed
Matthew B. Soellner, Bradley L. Nilsson, and Ronald T. Raines. Reaction mechanism and kinetics of the traceless Staudinger ligation J. Am. Chem. Soc. 2006 128 8820-8828 PubMed