Karus

A spin-out collaboration co-founded by Chemistry's Dr Ganesan and researchers based within Medicine for Cancer Research UK, Karus Therapeutics investigates the biological properties of a series of novel compounds for the treatment of cancer, inflammation and heart disease.

A spin-out collaboration co-founded by Dr Ganesan and researchers based at the Faculty of Medicine, Karus Therapeutics is focused on drug discovery. Karus Therapeutics is an emerging pharmaceutical company that is developing a new generation of small-molecules for the treatment of cancer and inflammation. Karus has assembled a team of world-class medicinal chemists and biologists that are generating new, potent and selective histone deacetylase (HDAC) inhibitors that offer significant clinical benefits and commercial potential.

Formed by the combination of leading chemistry and biology, Karus’s close association with the Cancer Research UK Clinical Center at Southampton General Hospital gives the company a strong clinical focus. This combination of clinical focus and scientific excellence is allowing Karus to make rapid progress in its drug discovery programs.

In eukaryotic cells, DNA is condensed into higher order structures called chromatin, in which the double-stranded DNA is tightly wrapped around proteins called histones. The ability of DNA to be transcribed is closely correlated with the degree of histone acetylation, a process that is regulated by a group of enzymes known as the histone acetyl transferases (HAT) and histone deacetylases (HDAC).

HDAC inhibitors are an important new class of drug, as they act selectively on diseased (e.g. cancerous) cells, whilst having little effect on normal, healthy cells. Histone deacetylases regulate the transcription of DNA and HDAC inhibitors have been shown to be potent anti-tumor agents. Histone deacetylases are a validated class of therapeutic target, with more than ten first-generation HDAC inhibitors currently in clinical trials and two FDA-approved drugs. Most of the early HDAC inhibitors are non-specific as they do not act selectively against certain classes of HDAC.

The selective inhibition of different classes of HDAC holds great promise for the treatment of diseases of abnormal gene activation including cancer, inflammation and neurodegeneration. Uniquely, Karus’s medicinal chemists have identified ways to engineer selectivity and potency into the depsipeptide class of HDAC inhibitors.

Depsipeptides are an important new class of HDAC inhibitor: they are potent, selective and exhibit a prolonged pharmacodynamic effect which is key to their clinical efficacy. The orginial depsipeptides are bacterial natural products that cannot be further optimized. Based on Dr. Ganesan’s research within the Chemistry department on depsipeptide total synthesis, Karus’s medicinal chemists have devised ways of engineering a new generation of depsipeptide HDAC inhibitors with specificity for different classes of HDAC. Karus is the first company in the world to generate synthetic analogues of depsipeptides. These insights are allowing Karus to synthesize HDAC inhibitors that are more potent, less toxic and have better drug-like properties than their predecessors. The work of Karus is an excellent illustration of the commercial potential of the ground breaking chemical research carried out within the University of Southampton.