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Anticancer Prodrugs and Pharmacogens

A major challenge for all anticancer drug classes is to achieve high cancer-selectivity of action. The depiction of all cancers as cells reproducing wildly (and therefore easily targetable by hindering successful cell replication) is a gross simplification. Many malignant tumours are actually slow-growing, and feature cellular biology and receptors / enzymes / antigens that are closely similar to their healthy tissue of origin; and only rarely are antimitotic/antiproliferative drugs selective enough to reliably achieve cancer remission.

We are using chemical biology designs to install new biochemically-triggered elements into known cancer drugs as well as boutique drugs that we design de novo. Our aim is to illustrate how extra layers of drug-targeting specificity can be built into compounds by using highly functionalised chemical "fuses", and how these can be translated into sensitive diagnostic or therapeutic tools for in vivo use.

The first avenue of research focuses on prodrugs that are substrates for naturally expressed proteins that are overactive in cancer tumours, and release a diagnostic (or ultimately therapeutic) drug, as shown in panel (a). Much work since the 1980s focussed on hydrolase-triggered prodrugs where an unmasked amine/hydroxyl "Q" moiety irreversibly cyclises and expels an active drug, but this has not proven a successful diagnostic/therapeutic strategy because the similarity of hydrolase expression profiles in tumours to those found in healthy cells decreases the selectivity. We instead focus on redox-active enzymes, which are known to be highly disregulated in cancers but which are also very poorly understood because of a lack of tools with which to study them selectively. We are essentially replacing the hydrolytically-unmasked QR trigger by nature's own biochemical redox substrates, and using a range of fluorescent reporters to create a colour panel of redox sensors. A particular challenge is to transition from irreversibly-triggered performance to ratiometric sensors: although with the reward, that these could offer more meaningful biological insight in certain important cases.

The second avenue of research focuses on what we term "pharmacogenic" prodrugs, as shown in panel (b). We have designed inactive compounds where a biochemically-triggered reaction cascade actually creates the crucial, bioactivity-installing bond network in situ inside a cell. Our proof-of-concept work uses cyclisation cascades to "refold" two pharmacophoric groups from a linear/extended inactive conformation in the precursor to a sterically unfavoured/crowded active conformation in the post-cascade species. Using a reporter fluorophore as the eliminated group (shown as "Drug 2" in the Figure above), we can monitor the pharmacogenic process in real time in living cells and measure the correlation to biological activity changes. Ultimately we imagine using this cascade to form a synergistic drug combination by choosing Drug 2's bioactivity to complement that of Drug 1.