The efficacy and tolerability of anticancer drugs are limited by their side effects. Controlling the activity of these drugs in space and time would allow improving chemotherapy treatments, and light-regulated drugs are well suited to this purpose. We have developed phototrexate, the first photoswitchable inhibitor of the human dihydrofolate reductase (DHFR), as an analogue of methotrexate, a widely prescribed chemotherapeutic drug to treat cancer and psoriasis. Quantification of the light-regulated DHFR enzymatic activity, cell proliferation, and in vivo effects in zebrafish show that phototrexate behaves as a potent antifolate in its photoactivated cis configuration and that it is nearly inactive in its dark-relaxed trans form. Thus, phototrexate constitutes a proof-of-concept to design light-regulated cytotoxic small molecules and a step forward to develop anticancer chemotherapies with localized efficacy and reduced adverse effects.
Reference
Matera C, Gomila AMJ, Camarero N, Libergoli M, Soler C & Gorostiza P 2018, ‘Photoswitchable Antimetabolite for Targeted Photoactivated Chemotherapy‘, J. Am. Chem. Soc., 140 (46), pp 15764–15773.
Methotrexate (orange) gets stuck in the active site of an important protein (DHFR) and is widely used as anticancer drug despite its side effects. The newly developed Phototrexate can inhibit DHFR under illumination (violet) and is nearly inert in the dark-relaxed form (blue).
