• Intracellular anti-apoptotic proteins
  
  In cancer cells, the expression level of various anti-apoptotic proteins is high compared to normal cells. As these proteins sequester pro-apoptotic protein mediators and proteases such as the caspases, natural programmed cell death is suppressed. Agents that selectively bind to and disrupt anti-apoptotic proteins will raise levels of pro-apoptotic proteins and caspases, and will result in tumor cell death and tumor shrinkage.
  
  Ensemble is using its proprietary DPC™ technology to advance programs against several anti-apoptotic proteins in the search for unprecedented drug-like macrocycles. Compounds that bind to these proteins will prevent the binding of pro-apoptotic mediators, freeing these mediators to promote the natural cell death of the cancer cells.
  
  
• Extracellular targets
  
  Many physiological and pathological processes are mediated by interactions of cytokines and growth factors with extracellular receptors. Several such receptors are validated for use in drug discovery but have only been targeted to date with large biological molecules (e.g. antibodies). Ensemble has initiated projects against several such targets and is prosecuting hit to lead studies against various inflammatory and cancer targets.

Many proteases ensure substrate specificity through extended binding motifs that make a large number of binding interactions with their peptidic substrates. Although this ensures the fidelity of protein substrate hydrolysis, drug discoverers have learned that finding small molecule inhibitors that bind with good affinity is very difficult, as successful compounds need to make a large number of relatively weak binding interactions to achieve a reasonable level of target affinity. For example, the aspartyl proteases renin and β-secretase (BACE) have each represented challenges for drug discovery using traditional medicinal chemistry.

Ensemble believes that macrocycles present a viable solution to the problem of finding potent protease inhibitors. The size and multiple functionality presented by macrocycles, combined with the structural pre-organization conferred by the ring, make these attractive starting points for drug discovery.

Protein tyrosine phosphatases (PTPs) represent a large family of enzymes that work with protein tyrosine kinases (PTKs) to play key roles in cellular signaling both inside and between cells. PTKs phosphorylate tyrosine residues on a substrate protein and PTPs remove these phosphates to change the activation state of the protein. PTP1B is a phosphatase that occurs widely in the body and negatively regulates insulin sensitivity by dephosphorylating the insulin receptor. Mechanistic studies have suggested that PTP1B inhibitors might serve as a novel class of ‘insulin sensitizer’ useful in the management of type 2 diabetes and metabolic syndrome.

Ensemble scientists have synthesized Ensemblins that inhibit PTP1B. The molecules are of an unprecedented class and mechanism, and are currently in the stage of hit to lead advancement.

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