2. Academic Validation
  3. Identification of Nitric Oxide Donating Dasatinib Derivatives with Intraocular Pressure Lowering and Senolytic Activities

Identification of Nitric Oxide Donating Dasatinib Derivatives with Intraocular Pressure Lowering and Senolytic Activities

  • J Med Chem. 2025 Apr 24;68(8):8600-8617. doi: 10.1021/acs.jmedchem.5c00269.
Zhongshu Pan 1 2,  Jiaming Zhang 1 2,  Haoyu Zuo 2,  Cunrui Li 1,  Huiying Song 2 3,  Haohan Yang 2,  Keling Wu 2,  Minglei Zhao 2,  Zirong Zhang 2,  Yuhua Lai 2,  Jingyi Luo 2,  Jianbing Wu 1,  Ling Zhao 2,  Zhangjian Huang 1 4
Affiliations

Affiliations

  • 1 State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Drug Discovery, China Pharmaceutical University, Nanjing 210009, P. R. China.
  • 2 State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology Visual Science, Guangzhou 510060, P. R. China.
  • 3 Guangdong Province Key Laboratory of Brain Function and Disease, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510000, P. R. China.
  • 4 School of Pharmacy, Xinjiang Key Laboratory of Biopharmaceuticals and Medical Devices, Key Laboratory of Active Components of Xinjiang Natural Medicine and Drug Release Technology, Engineering Research Center of Xinjiang and Central Asian Medicine Resources, Xinjiang Medical University, Urumqi 830054, P. R. China.
PMID: 40228166 DOI: 10.1021/acs.jmedchem.5c00269
Abstract

Based on two major risk factors of glaucoma, elevated intraocular pressure (IOP) and senescence, two new series of nitric oxide (NO) donating dasatinib derivatives 1a-f, 2a-f were designed, synthesized, and biologically evaluated. The results demonstrated that the most active compound 2e effectively released NO and increased the concentration of 3',5'-cyclic guanosine monophosphate in human trabecular meshwork cells, as well as maintained senolytic activity. Topical administration of 2e in chronic ocular hypertension (COHT) glaucoma mice not only significantly eliminated senescent cells in retina but also exhibited potent retinal ganglion cells (RGCs) surviving, IOP lowering, and visual function protection activities, which were superior to those of dasatinib. Compared with younger adult mice, aged COHT mice resulted in more severe RGCs loss, while 2e demonstrated a greater capacity to improve RGCs survival. Our findings show that dual IOP lowering and senolytic functions could be a promising therapeutic strategy for glaucoma, particularly in older patients.

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