Self-Assembled Cryptate Kinase Inhibitors as Anti-Cancer Therapeutic Agents.

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Whilst there have been considerable achievements in the development of new cancer drugs that are 'targeted' at key processes involved in cancer biology, the reality is that many cancers remain hard to treat. Although targeted anti-cancer drugs have had a major impact on the treatment of cancers, the clinical effectiveness of all 37 kinase inhibitors (compounds that inhibit important enzymes that drive cancer cell replication) currently approved by the FDA is severely compromised by problems with drug resistance and toxicity. To override the current limitations of kinase inhibitors, we have developed and tested a limited number of compounds called 'trimetallic cryptands' composed of a ligand (L) and a metal (M) that can encapsulate a range of anions (A). By mixing M, L and/or A together in various combinations, a series of cryptands are formed by a process known as self-assembly. The self-assembled cryptands can inhibit multiple kinases and are selectively toxic to cancer cells compared to non-cancer cells. The ability to target multiple kinases whilst retaining selectivity for cancer cells is an important finding because (i) cancer cells will find it difficult to develop resistance as multiple pathways are being 'hit' which differs from current kinases inhibitors that target just one or a limited number of pathways and (ii) the ability to selectively kill cancer cells suggests that a 'therapeutic window' exists where cancer cells are killed with limited damage to normal tissues. As we have only developed a limited number of cryptands, the principle aim of this project is to make more compounds that can be tested to identify new 'hits' that are selectively toxic to cancer cells. As cryptands are made up of M, L and A, mixing different 'flavours' of each component part together so that they self-assemble to form cryptands with different pharmacological properties could generate many therapeutically active drugs from a relatively small number of 'ingredients'. To use a popular analogy, a specific cocktail is made up of several component parts which when blended together gives a characteristic taste. The recipe can be varied to produce a range of different cocktails, each of which has a specific flavour. Our approach uses a range of different chemical ingredients which when combined can give a 'therapeutic cocktail' that has a specific effect with each cocktail having different effects. In the future, it may be possible to target many cancers through this approach with the correct drug 'self-assembled' in such a manner as to be selective for a cancer type or an individual patient's cancer. By exploring the 'chemical space' and developing more chemical 'ingredients' that can be self-assembled to form drugs with different properties, we have the potential to expand the range of potential drugs that we have available to develop. Understanding the chemical properties of these compounds and their activity in the laboratory is an essential step that will drive this work forward where the aim is to be able to design 'therapeutic cocktails' that will specifically target hard to treat cancers, are selectively active to cancer cells and do not suffer from the emergence of drug resistance. The ultimate aim is to be able to assemble drugs at the patient's bedside that will target key biochemical features in that individual patient's cancer resulting in anti-tumour activity and prolonged life.