Phototrexate : a novel drug candidate for cancer and psoriasis

Antifolates are structural analogs of folates, essential one-carbon donors in the synthesis of DNA in mammalian cells, and they work as inhibitors of key enzymes in folate metabolism, such as dihydrofolate reductase and thymidylate synthetase. Methotrexate (MTX) was one of the first agents of this class and is still extensively used in the treatment of a variety of tumors, including acute lymphocytic leukemia, breast cancer, osteosarcoma, primary central nervous system lymphoma, and head and neck cancer. Above all, it is also commonly used in certain autoimmune diseases, such as rheumatoid arthritis or psoriasis. However, the clinical efficacy of MTX is often limited and compromised by toxic dose-related side effects, which leads to morbidity, interruption of the treatment, and occasional mortality. A promising approach to tackle this problem is to activate the drug exclusively at its desired place of action. In fact, in those diseases that would benefit from a highly localized treatment, a precise spatiotemporal control over the activity of a chemotherapeutic agent would allow reducing the concentration of active compound outside the target tissue, improving the tolerability and hence the efficacy of the treatment. Light is a powerful tool in this respect: it offers unparalleled opportunities as a non-invasive regulatory signal for pharmacological applications because it can be delivered with high precision regarding space, time, intensity and wavelength. We have recently developed Phototrexate, the first photoswitchable antifolate, by incorporation of a photochromic unit into the structure of MTX. Phototrexate was designed to be constitutively inactive in its thermodynamically stable configuration (E isomer), while it can be activated with light (Z isomer) to locally provide the pharmacological effects of the parent drug, as confirmed in our earlier experiments in vitro and in zebrafish larvae. Studies are currently underway to assess safety/tolerability, pharmacokinetics, pharmacodynamics, and efficacy of our compound in vitro and in preclinical animal models. All current results indicate that Phototrexate is a drug candidate with high potential for development as an innovative light-regulated antifolate for cancer and psoriasis.