A photoactivatable prodrug strategy toward spatially targeted inhibition of POLRMT for anticancer therapy.

Mitochondrial RNA polymerase (POLRMT) is overexpressed in multiple cancer types and has emerged as a viable therapeutic target. Inhibition of POLRMT disrupts mitochondrial transcription and impairs oxidative phosphorylation (OXPHOS), ultimately suppressing cancer cell proliferation. However, conventional POLRMT inhibitors may also affect normal tissues with high metabolic demands, posing a potential risk of energy deficiency. In this study, we designed and synthesized a series of photoactivatable POLRMT inhibitors. The lead compound, J5, exhibits biological inertness in the dark and rapidly liberates the active parent molecule LJ03 upon irradiation, enabling spatiotemporally precise POLRMT inhibition and localized antitumor efficacy. Controlled release of LJ03 was achieved through optimization of illumination parameters, which significantly improved tissue selectivity. The antiproliferative activity of J5 was further validated in a zebrafish xenograft model. Collectively, this work demonstrates the feasibility of photoactivated POLRMT inhibitors for enhancing the safety profile of POLRMT-targeting agents, highlighting a potential avenue for future precision oncology applications.