Two-Photon Photodegradation of E3 Ubiquitin Ligase Cereblon by a Ru(II) Complex: Inducing Ferroptosis in Cisplatin-Resistant Tumor Cells

  • J Med Chem. 2024 May 23;67(10):8372-8382. doi: 10.1021/acs.jmedchem.4c00545.
Xinlin Lin  1 ,  Mengsi Zheng  1 ,  Kai Xiong  1 ,  Fa Wang  1 ,  Yu Chen  1 ,  Liangnian Ji  1 ,  Hui Chao  1
Affiliations
  • 1. MOE Key Laboratory of Bioinorganic and Synthetic Chemistry, Guangdong Basic Research Center of Excellence for Functional Molecular Engineering, School of Chemistry, Sun Yat-Sen University, Guangzhou 510006, P. R. China.
PMID: 38745549 DOI: 10.1021/acs.jmedchem.4c00545
Abstract

Using photodynamic therapy (PDT) to trigger nonconventional cell death pathways has provided a new scheme for highly efficient and non-side effects to drug-resistant Cancer therapies. Nonetheless, the unclear targets of available photosensitizers leave the manner of PDT-induced tumor cell death relatively unpredictable. Herein, we developed a novel Ru(II)-based Photosensitizer, Ru-Poma. Possessing the E3 ubiquitin Ligase CRBN-targeting moiety and high singlet oxygen yield of 0.96, Ru-Poma was demonstrated to specifically photodegrade endogenous CRBN, increase lipid peroxide, downregulate GPX4 and GAPDH expression, and consequently induce Ferroptosis in cisplatin-resistant cancerous cells. Furthermore, with the deep penetration of two-photon excitation, Ru-Poma achieved drug-resistant circumvention in a 3D tumor cell model. Thus, we describe the first sample of the CRBN-targeting Ru(II) complex active in PDT.

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