Over-expression of the DNA repair enzyme O6-methylguanine-DNA methyltransferase (MGMT) diminishes the effects of the common anti-cancer alkylating agent, temozolomide (TMZ). By employing inhibitors of MGMT, such as O6-benzylguanine or PaTrin-2, the therapeutic effects of TMZ have been shown to substantially increase. However, MGMT inhibitors are not cancer selective and as a result, MGMT is inhibited in all cells leading to normal cell toxicity post TMZ administration. To this regard, we are modifying MGMT inhibitors with photoremovable protecting groups such that they are inactive against MGMT in the dark. By confining light irradiation to cancer cells only, the inhibitors can be activated to inhibit MGMT, thereby increasing the effects of TMZ with reduced toxicity to normal cells. Using a fluorescence-based MGMT activity assays, we have established that photocaging these inhibitors diminishes their inhibitory effect on MGMT, while irradiation recovers their native inhibition. Additionally, our modified inhibitors were tested <i>in cellulo</i>alongside TMZ where cancer cell death was shown to be significantly lower when compared to cancer cells treated with MGMT inhibitors and TMZ. Upon irradiation with light, cancer cell death was increased indicating that inhibition of MGMT was successfully achieved. Thus, photocaging inhibitors of anti-cancer therapy may be a useful strategy for improving the efficacy of anti-cancer drugs such as TMZ. <br/>

Photoactivation of inhibitors of anti-cancer therapy

2019 Spring National Meeting

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