Ensemble is focused on the discovery and development of breakthrough small molecule therapies for patients with cancer and other serious diseases. We are leveraging our proprietary drug discovery platform to develop novel small molecules to drug well-validated, challenging disease targets that are not currently addressed by regular small molecules or antibodies. Our growing pipeline is comprised of synthetic macrocycles and other creative small molecules that expand the boundaries of traditional therapeutics to address important disease targets inside and outside of cells.

Immune Checkpoint Programs

Immune checkpoints suppress the immune system and may prevent an appropriate immune response resulting in a variety of cancers.  Several approved antibody drugs targeting immune checkpoints have demonstrated promising benefit in treating certain cancers by prolonging an immune response to the cancer.  Small molecule drugs targeting immune checkpoints may complement current antibody therapies and provide unique advantages including safety, efficacy, and more convenient administration. 

  • Safety: shorter half-life will minimize the duration of any adverse events
  • Efficacy:  small molecule size may penetrate solid tumors better
  • Administration:  potential for oral and other non-injectable routes

IDO-1 is an immune checkpoint that suppresses the immune system and prevents an appropriate immune response to cancer.  Ensemble used its drug discovery platform to find novel, target-specific IDO drugs that may provide unique advantages over other IDO drugs. 

Other Programs

USP9x:  Ubiquitination and phosphorylation regulate most aspects of cell function.  Defects in these mechanisms cause cancer and other diseases. Kinases modulate phosphorylation and are an important class of drug targets.  Deubiquitinases (DUBs) modulate ubiquitination and have the potential to be as important a class of drug targets as kinases.  DUBs modulate the levels of many key oncogenic proteins, and are therefore attractive drug targets for many cancers.  Inhibiting DUBs increases the degradation of oncogenic proteins, an exciting new approach to treating cancer.

Usp9x plays an essential role in the survival of highly metastatic tumors, including melanoma, glioblastoma, medulloblastoma, triple-negative breast and pancreatic tumors.  Blocking USP9x function has been shown to be effective in suppressing or regressing in vivo tumor growth and blocking metastases.  Ensemble has identified several novel macrocyclic compound series that inhibit USP9x.

Cyclophilin:  Cyclophilins are a broad family of proteins with diverse functions similar to the kinase family, thus offering promising drug targets to treat a variety of diseases.  Cyclophilins differ in their developmental, cellular, and subcellular expression and in their intracellular binding partners.  Broad-based inhibitors, including natural toxins, are likely to have off-target effects causing toxicity.  Ensemble has discovered novel compounds that are more specific inhibitors of members of the cyclophilin family.

Cyclophilin A is the principal cyclophilin involved in the Hepatitis B virus (“HBV”) surface antigen production and secretion. The therapeutic effects of cyclophilin inhibition on HBV life cycle is supported by in vitro and in vivo animal data. Inhibitors of cyclophilin D have been investigated for neurodegenerative disorders (e.g. Alzheimer's, Parkinson's), and reperfusion injury (e.g. myocardial infarction, stroke, TBI).

Ensemble has discovered multiple series of compounds inhibiting cyclophilin A and D in both macrocyclic and ‘small molecule’ series.  Our compounds represent totally novel and unprecedented cyclophilin binders with structural insights into their binding modes.  They have promising physical properties including proven PAMPA membrane permeability.

IAP:   IAPs including both XIAP and cIAP are a family of cancer-promoting proteins that can inhibit tumor cell death by regulating the caspase enzymes that cause apoptosis. Elevated expression of IAPs has been reported in many cancers and is associated with poor prognosis. Ensemble has discovered an unprecedented series of macrocycles that inhibit various forms of IAP and have demonstrated tumor growth inhibition in animal models.

MDM2/p53:  MDM2 is an E3 ubiquitin ligase that targets p53 for destruction by the proteasome. As p53 is a tumor suppressor, blocking MDM2:p53 has been shown to limit cellular proliferation and enhance anti-cancer activity.  We have identified several novel macrocyclic compound series that block the MDM2:p53 interaction. These compounds are validated MDM2:p53 antagonists and are demonstrated inhibitors of p53 ubiquitination by MDM2.

[ back to top ]