Anti tumour agents from natural products - new approaches to targeting ultra potent analogues of the duocarmycins

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Molecules that kill cells that divide, known as cytotoxic drugs, are still the backbone of clinically used chemotherapeutic agents against cancer. The problem is that these compounds are very toxic. They kill all dividing cells in the body and so lead to horrendous and debilitating side effects in patients that are already very ill. In the last twenty years, the focus for the design of new agents has switched to two main approaches in order to try to curtail these side effects - either targeting tumour specific pathways or through targeting of cytotoxic agents so that they only exert their effects at the desired site of action. Both approaches have met with some success. In the former case, the antibody called trastuzumab (trade name herceptin) is well known and is used in the treatment of breast cancer. It targets a receptor called Her2, which is highly over-expressed on the surface of some tumour cells and therefore the agent is selective for those tumours. Similarly, the kinase inhibitor imatinib mesylate (gleevec or glivec) targets a protein in chronic myeloid leukaemia and is now used in the treatment of this disease. These compounds kill cells in a selective way at the protein level. What if we could target ultrapotent drugs at the level of genes, so before any protein has been produced? We have recently developed methodology to rapidly generate analogues of the estremely potent natural products the duocarmycins using solid phase synthesis and are investigating the development of antibody drug conjugates (ADCs) and protein targeting based upon these molecules. However, there are other potential targeting methodologies that we now aim to investigate. This involves the selective targeting of particular genes via the incorporation of duocarmycins into selective molecules that bind to particular sequences of double stranded DNA and have the potential to turn off particular genes. These are called distamycin analogues or "hairpin polyamides". While simply attaching a duocarmycin analogue to a gene selective agent by a linker has been studied, the incorporation of the duocarmycin into the polyamide has only become a realistic proposition with the development of our approach. The ability to turn off particular genes through selective DNA alkylation will be a powerful approach to the development of targeted agents and will help in the identification of new molecules with potential in the treatment of disease, including cancer.