The development of new drugs to treat cancer can be a slow and costly journey. Drug repurposing can be an attractive strategy for speeding up drug discovery. This approach involves identifying new therapeutic uses for existing drugs that have already been found safe and effective, without the time-consuming and costly process of developing entirely new drugs.

Ming-Wei Chen, Curamir Therapeutics, Inc., Woburn, MA, USA, have investigated whether tranylcypromine (TCP), a monoamine oxidase inhibitor commonly used as an antidepressant, can be repurposed for cancer therapy. TCP could be useful against cancer due to its ability to inhibit the lysine-specific demethylase 1 (LSD1) enzyme. However, TCP’s limited potency and specificity towards LSD1 make it unsuitable as a standalone cancer drug. Nevertheless, a combination with other drugs could lead to an anti-cancer combination therapy.

The team used a CRISPR-Cas9 knock-out (KO) strategy to edit eight potential drug targets in cancer cell lines. They then screened the possible targets by applying TCP to the CRISPR-knocked-out cells. If the cells died, it showed that TCP and a drug that would inhibit the knocked-out target could work together against cancer. The nuclear factor erythroid 2-related factor 2 (NRF2) target was found to be the most promising target for a combination of TCP with a second drug.

The team found that ML385, an NRF2-inhibitor drug, showed synergistic effects in combination with TCP. A combination of TCP and ML385 resulted in a significant reduction in tumor growth, while neither drug affected cancer cell growth meaningfully on its own. According to the researchers, further studies are needed to understand the underlying mechanism of this effect and the potential side effects. Overall, the work could be useful for the development of an effective combination cancer therapy.

• Synergistic Effects of Tranylcypromine and NRF2 inhibitor: A Repurposing Strategy for Effective Cancer Therapy,
  Delos Chen, Skye Chen, Fangheng Zhou, Lan Bo Chen, Ming-Wei Chen,
  ChemMedChem 2023.
  https://doi.org/10.1002/cmdc.202300282