In addition to Ensemble’s immuno-oncology and ubiquitin proteasome system pipeline programs, we have also been successful in demonstrating the effectiveness of macrocycles in binding to other important disease targets. There are several other preclinical programs in development including cyclophilin and IAP antagonist programs.
The inhibitors of apoptosis (IAP) proteins, including both XIAP and cIAP, are a family of cancer-promoting proteins that can inhibit tumor cell death by binding to the caspase enzymes that cause apoptosis. Elevated expression of IAPs has been reported in many cancers and is associated with poor disease prognosis.
Ensemble has discovered a novel series of macrocycles with affinity for various forms of IAP and demonstrated caspase release and tumor growth inhibition in animal models.
Cyclophilins are a broad family of proteins with diverse functions, but are primarily responsible for the isomerization of peptide bonds and thus facilitate protein folding. There is considerable evidence that drugs binding to cyclophilins offer the potential to treat a variety of diseases.
Cyclophilin A is the principal cyclophilin involved in the Hepatitis B virus (HBV) surface antigen production and secretion. Inhibitors therefore have potential utility in the treatment of HBV infection. Inhibitors of Cyclophilin D have been investigated for neurodegenerative disorders (e.g. Alzheimer’s, Parkinson’s), and reperfusion injury (e.g. myocardial infarction, stroke, traumatic brain injury).
Ensemble has discovered multiple series of compounds inhibiting Cyclophilin A and D in both macrocyclic and ‘small molecule’ series. Our compounds represent completely novel and unprecedented molecular classes of Cyclophilin binders.