1 Department of Chemical and Physical Sciences, University of Toronto Mississauga, Mississauga, Ontario L5L 1C6, Canada.
2 Department of Chemistry and Biochemistry, Concordia University, 7141 Sherbrooke St. W., Montréal, Québec H4B 1R6, Canada.

The DNA repair enzyme O⁶-Methylguanine DNA Methyltransferase (MGMT) is a major contributor in conferring resistance to alkylating agents such as temozolomide (TMZ) in cancers. The use of MGMT inhibitors can suppress resistance and enhance the efficacy of TMZ. However, current inhibitors are nonselective for cancer cells, and as a result, MGMT is also inhibited in healthy cells leading to severe side effects. Here, we report the development of a photoactivatable MGMT inhibitor, whereby irradiation is required for MGMT inhibition and subsequent enhancement of the TMZ sensitivity in T98G cells. This strategy is promising for tissue-specific therapy, whereby TMZ efficacy can only be enhanced in the cancerous region and not healthy tissue, controlled spatially by light.