2. Academic Validation
  3. Novel PHD2/HDACs hybrid inhibitors protect against cisplatin-induced acute kidney injury

Novel PHD2/HDACs hybrid inhibitors protect against cisplatin-induced acute kidney injury

  • Eur J Med Chem. 2022 Feb 15;230:114115. doi: 10.1016/j.ejmech.2022.114115.
Huiqiang Wei 1,  Wenfeng Gou 1,  Jun Gao 2,  Hongxin Ning 1,  Yang Song 3,  Deguan Li 1,  Yong Qin 4,  Wenbin Hou 5,  Yiliang Li 6
Affiliations

Affiliations

  • 1 Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, Peking Union Medical College & Chinese Academy of Medical Sciences, Tianjin, 300192, China.
  • 2 Shengyang Pharmaceutical University, Shenyang, 110016, China.
  • 3 Department of Pathology, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, 121000, China.
  • 4 Department of Pharmaceutical Sciences, The University of Texas at El Paso, El Paso, TX, United States. Electronic address: yqin@utep.edu.
  • 5 Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, Peking Union Medical College & Chinese Academy of Medical Sciences, Tianjin, 300192, China. Electronic address: houwenbin@irm-cams.ac.cn.
  • 6 Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, Peking Union Medical College & Chinese Academy of Medical Sciences, Tianjin, 300192, China. Electronic address: liyiliang@irm-cams.ac.cn.
PMID: 35033824 DOI: 10.1016/j.ejmech.2022.114115
Abstract

Acute kidney injury (AKI) is associated with high morbidity and mortality. Cisplatin is a common chemotherapeutic, but its nephrotoxicity-driven AKI limits its clinical application. Currently, there are no specific and satisfactory therapies in the clinic for AKI. Inhibitors of hypoxia-inducible factor prolyl hydroxylase 2 (HIF-PHD2) or histone deacetylase (HDACs) had shown renoprotective effects against AKI in preclinical studies. This study aimed to develop a novel therapeutic to prevent AKI progression by targeting PHD2 and HDACs simultaneously. We designed and synthesized a series of PHD2/HDACs hybrid inhibitors. The initial drug activity screening identified a candidate compound 31c, which exhibited potent inhibitory activities against PHD2 and HDAC1/2/6. Cellular analyses further showed that 31c did not affect cisplatin's antitumor activity in Cancer cells but strongly protected cisplatin-induced toxicity on HK-2 cells. In vivo studies with the cisplatin-induced AKI mouse model demonstrated that 31c remarkably alleviated kidney dysfunction with suppressed plasma BUN/SCr and increased EPO levels. The potent renoprotective effects of 31c on AKI were confirmed by significant improvements in pathological kidney conditions in the mouse model. These results suggest that the novel PHD2/HDACs hybrid inhibitor, 31c, has a clinical potential as the renoprotective agent for the treatment/prevention of cisplatin-induced AKI for various cancers.

Keywords

Acute kidney injury; HDACs; Hybrid inhibitor; PHD2; Renal protecting.

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