Boston Biochem in Nature

If you pick up the October 26th issue of Nature you might notice a letter titled "USP7 Small Molecule Inhibitors Interfere with Ubiquitin Binding."  The paper, submitted by Genentech scientists Ingrid E. Wertz and Till Maurer, is the culmination of more than two years of collaborative research carried out at Genentech, UCSF, University of Dundee, Newcastle University and Boston Biochem (Bio-Techne, Cambridge).

USP7 is a specialized cysteine protease belonging to a class of enzymes known as deubiquitinases, or "DUBs."  There are roughly 100 known DUBs in humans, and imbalances in DUB activity are frequently a contributing factor in the development and progression of disease states including Alzheimer's, Parkinson's, chronic inflammation, and many malignancies.  USP7 plays a critical role in regulating the stability of the p53 tumor suppressor protein, and inhibition of USP7 induces apoptosis of some tumor cells and enhances the cytotoxicity of chemotherapeutic agents.  Thus, small molecule inhibition of USP7 and other DUBs provides a potential means to treat significant human ailments, but developing selective deubiquitinase inhibitors has proven extremely difficult for heavyweights in the field including Genentech, Forma, Almac, Mission Therapeutics and others. 

The letter describes the development of selective USP7 inhibitors GNE-6640 and 6776, and provides one of the first published structures of small molecule inhibitors bound to this class of enzymes.  Boston Biochem researchers Dr. Carsten Schwerdtfeger and Zac Stiffler devoted many long nights engineering di-ubiquitin chains containing differential proximal and distal isotopic (15N) labels.  These reagents were essential for imaging the USP7-inhibitor complexes using nuclear magnetic resonance-based (2D-NMR) techniques.  At a recent celebration hosted by Genentech, Dr. Maurer praised Carsten and Zac's efforts saying that the labeled di-ubiquitin chains are "…a very elegant piece of work that's already drawing interest from other NMR specialists in the field."  

Together with similar recent reports, the data support the concept that some deubiquitinases will indeed be druggable targets for therapeutic intervention.

You can read the letter, "USP7 Small-Molecule Inhibitors Interfere with Ubiquitin Binding" here.