2. Academic Validation
  3. A novel mitochondria-targeting DHODH inhibitor induces robust ferroptosis and alleviates immune suppression

A novel mitochondria-targeting DHODH inhibitor induces robust ferroptosis and alleviates immune suppression

  • Pharmacol Res. 2024 Apr:202:107115. doi: 10.1016/j.phrs.2024.107115.
Yongrui Hai 1,  Renming Fan 1,  Ting Zhao 2,  Ruizhuo Lin 1,  Junyan Zhuang 1,  Aohua Deng 1,  Shanshui Meng 3,  Zhuang Hou 4,  Gaofei Wei 5
Affiliations

Affiliations

  • 1 Institute of Medical Research, Northwestern Polytechnical University, Xi'an 710072, China; Research & Development Institute of Northwestern Polytechnical University in Shenzhen, 518057, China.
  • 2 School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang 110016, China.
  • 3 School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China. Electronic address: [email protected].
  • 4 School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang 110016, China. Electronic address: [email protected].
  • 5 Institute of Medical Research, Northwestern Polytechnical University, Xi'an 710072, China; Research & Development Institute of Northwestern Polytechnical University in Shenzhen, 518057, China. Electronic address: [email protected].
PMID: 38423231 DOI: 10.1016/j.phrs.2024.107115
Abstract

Dihydroorotate Dehydrogenase (DHODH)-mediated Ferroptosis defense is a targetable vulnerability in Cancer. Currently, only a few DHODH inhibitors have been utilized in clinical practice. To further enhance DHODH targeting, we introduced the mitochondrial targeting group triphenylphosphine (TPP) to brequinar (BRQ), a robust DHODH inhibitor, resulting in the creation of active molecule B2. This compound exhibits heightened Anticancer activity, effectively inhibiting proliferation in various Cancer cells, and restraining tumor growth in melanoma xenografts in mice. B2 achieves these effects by targeting DHODH, triggering the formation of Reactive Oxygen Species (ROS), promoting mitochondrial lipid peroxidation, and inducing Ferroptosis in B16F10 and A375 cells. Surprisingly, B2 significantly downregulates PD-L1 and alleviates immune suppression. Importantly, B2 exhibits no apparent adverse effects in mice. Collectively, these findings highlight that enhancing the mitochondrial targeting capability of the DHODH inhibitor is a promising therapeutic approach for melanoma treatment.

Keywords

Anticancer; DHODH inhibitor; Ferroptosis; Melanoma; Mitochondrial-targeting.

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