Can Inhibiting Ubiquitin Target Undruggable Tumor Proteins?

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A class of DUBs known as the ubiquitin-specific-processing proteases are involved in regulating the p53 signaling pathway and have been implicated in tumorigenesis and radiotherapy resistance.
A class of DUBs known as the ubiquitin-specific-processing proteases are involved in regulating the p53 signaling pathway and have been implicated in tumorigenesis and radiotherapy resistance.

Ubiquitin is a regulatory protein found in most eukaryotic cell types. It is involved in targeting other proteins for destruction by the cellular proteasome “garbage disposal” system, and thereby helps to regulate key cellular processes such as cell cycle, DNA transcription and cellular division, apoptosis, and DNA repair.3-5

Ubiquitination (attaching ubiquitin to targeted protein complexes) and deubiquitination (the enzymatic cleaving ubiquitin from proteins) are involved in p53 and MDM2 signaling. Deubiquitinating enzymes (DUBs) are involved in cellular hypoxia responses and radioresistance.4

DUB mutations are frequently found in tumors, leading some researchers to believe that deregulation of ubiquitination and deubiquitination contributes to tumorigenesis.4 These enzymes are also implicated in cancer stem cells' “stemness,” differentiation, and cell fate determination.6

Because many supposedly “uninhibitable” or “undruggable” oncoproteins are degraded via ubiquitination in healthy cells and because ubiquitination-dependent degradation is destabilized in tumor cells, some researchers suspect that salvaging or enhancing ubiquitination might be a new way to “drug the undruggables” to disrupt tumor progression.7

Efforts are therefore under way to develop ubiquitin pathway-targeting agents as anticancer therapies, including drugs that modulate a class of DUBs known as the ubiquitin-specific-processing proteases (USPs). Several investigative selective inhibitors of ubiquitin-specific-processing protease 7 (USP7; a DUB also known as herpes virus–associated ubiquitin specific protease, or HAUSP) are under development as potential anticancer agents.

USP7 inhibition holds particular promise as an anticancer strategy because USP7 stabilizes MDM2, the oncogenic E3 ligase that destabilizes the p53 tumor suppressor protein, explained Wei Zhang, PhD, of the University of Toronto in Canada. USP7 inhibition causes MDM2 degradation and re-activation of p53 in different cancer cell lines.

That makes USP7 “crucial for cancer cell survival,” Dr Zhang noted. “The first generation of USP7 inhibitors in general has low (mid-micromolar) potency and cellular specificity and poor pharmacological properties.”

Dr Zhang and colleagues are using a synthetic biology technique called structure-based combinatorial protein engineering to develop inhibitors for USP7 and USP10 as potential anticancer agents.8,9

They're not alone. Researchers around the world are racing to develop other USP7 inhibitors as investigational cancer treatments.1,2,10

Genentech has developed 2 USP7 inhibitors, known as GNE-6640 and GNE-6776, which improved chemotherapeutic effects against cancer cells. “These compounds induce tumour cell death and enhance cytotoxicity with chemotherapeutic agents and targeted compounds, including PIM kinase inhibitors,” they reported.1

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