2. Academic Validation
  3. A photoactivatable prodrug strategy toward spatially targeted inhibition of POLRMT for anticancer therapy

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

  • Eur J Med Chem. 2026 Feb 15:304:118537. doi: 10.1016/j.ejmech.2025.118537.
Lijuan Huang 1,  Yunyue Wang 1,  Minghui Yu 1,  Xinyang Nie 1,  Yifan Yuan 1,  Bao He 2,  Zhixiang Sun 2,  Jinyi Xu 1,  Lei Shi 3,  Hong Yao 4,  Xinnan Li 5
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 211198, PR China.
  • 2 Department of Neurosurgery, Affiliated Kunshan Hospital of Jiangsu University, China Medical University, Gusu School, Nanjing Medical University, Suzhou, PR China.
  • 3 Department of Neurosurgery, Affiliated Kunshan Hospital of Jiangsu University, China Medical University, Gusu School, Nanjing Medical University, Suzhou, PR China. Electronic address: [email protected].
  • 4 Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 211198, PR China. Electronic address: [email protected].
  • 5 Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 211198, PR China. Electronic address: [email protected].
PMID: 41478007 DOI: 10.1016/j.ejmech.2025.118537
Abstract

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.

Keywords

Antitumor; Mitochondrion; OXPHOS; POLRMT inhibitors; Photopharmacology.

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