Ubiquitin Proteasome System Programs

Ubiquitination and phosphorylation are important regulatory functions in all cells. Defects in these mechanisms have been linked to cancer and other serious diseases. Kinases are a class of enzyme that modulate phosphorylation and have been successfully exploited as drug targets for treating cancer. Similarly, deubiquitinases (DUBs), members of the ubiquitin proteasome system (UPS), modulate ubiquitination and have the potential to be as important a class of drug targets as kinases. Inhibiting DUBs results in the degradation of oncogenic proteins and provides an exciting new approach to treating cancer.

Using our proprietary discovery platform, Ensemble has rapidly identified multiple highly specific DUB inhibitors to USP9X, USP28 and USP30 targets.


Ubiquitin-specific protease 9x (USP9x) plays an essential role in elevating levels of oncoprotein MCL1, which causes the survival of highly metastatic tumors, including melanoma, glioblastoma, and triple-negative breast and tumors. Blocking USP9x function has been shown to be effective in suppressing or regressing tumor growth and blocking metastases.

Ensemble has identified several novel small molecule compound series that are potent and selective inhibitors of USP9x that bind to an allosteric site on the enzyme. We are currently progressing this program towards a development candidate.


The oncoprotein c-MYC is poorly regulated in a number of cancers leading to tumor cell proliferation. Since c-MYC is difficult to target directly with existing small molecule therapeutics, an alternative strategy is to inhibit ubiquitin-specific protease 28 (USP28) which plays a role in stabilizing c-MYC.

Ensemble has discovered novel inhibitors of USP28 with the potential to accelerate c-MYC degradation and reduce tumor size.


Inhibitors of ubiquitin-specific peptidase 30 (USP30) have the ability to speed up the breakdown of a oncoprotein known as mitochondrial TOM20. Reducing levels of this oncoprotein can provide a mechanism for treating renal and pancreatic cancer. There is evidence demonstrating that reducing USP30 activity would enhance degradation of damaged mitochondria in neurons and is potentially beneficial for treating Parkinson’s disease.

Ensemble has discovered novel inhibitors of USP30 with potential utility for both cancer and Parkinson’s disease.