2. Academic Validation
  3. Discovery of highly potent and selective VEGFR2 kinase inhibitors for the treatment of rheumatoid arthritis

Discovery of highly potent and selective VEGFR2 kinase inhibitors for the treatment of rheumatoid arthritis

  • Eur J Med Chem. 2023 Sep 5;257:115456. doi: 10.1016/j.ejmech.2023.115456.
Qingling Chen 1,  Zhuoying Chen 1,  Feilong Li 1,  Haoyu Zha 1,  Wei He 1,  Fei Jiang 1,  Jiamu Wei 1,  Jiajia Xu 1,  Rong Li 2,  Li Cai 3,  Xuesong Liu 4
Affiliations

Affiliations

  • 1 Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, School of Pharmacy, Anhui Medical University, Hefei, 230032, Anhui Province, PR China.
  • 2 Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, School of Pharmacy, Anhui Medical University, Hefei, 230032, Anhui Province, PR China; Institute of Health and Medicine, Hefei Comprehensive National Science Center, Hefei, 230026, Anhui Province, PR China. Electronic address: aydlirong@163.com.
  • 3 Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, School of Pharmacy, Anhui Medical University, Hefei, 230032, Anhui Province, PR China; Department of Pathology, School of Basic Medicine, Anhui Medical University, Hefei, 230032, Anhui Province, PR China. Electronic address: sdcaili@163.com.
  • 4 Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, School of Pharmacy, Anhui Medical University, Hefei, 230032, Anhui Province, PR China. Electronic address: chemxsliu@126.com.
PMID: 37216810 DOI: 10.1016/j.ejmech.2023.115456
Abstract

Synovial angiogenesis is essential for the development of rheumatoid arthritis (RA). Human vascular endothelial growth factor receptor 2 tyrosine kinase (VEGFR2/KDR/Flk-1) is a direct target gene that is notably elevated in RA synovium. Herein, we report the identification of indazole derivatives as a novel class of potent VEGFR2/KDR/Flk-1 inhibitors. The most potent compound, compound 25, displayed single-digit nanomolar potency against VEGFR2/KDR/Flk-1 in biochemical assays and achieved good selectivity for other protein kinases in the kinome. In addition, compound 25 dose-dependently inhibited the phosphorylation of VEGFR2/KDR/Flk-1 in Human Umbilical Vein Endothelial Cells (HUVECs) and showed an anti-angiogenic effect, as evidenced by the inhibition of capillary-like tube formation in vitro. Moreover, compound 25 reduced the severity and development of adjuvant-induced arthritis in rats by inhibiting synovial VEGFR2/KDR/Flk-1 phosphorylation and angiogenesis. Overall, these findings provide evidence that compound 25 is a leading potential drug candidate for anti-arthritic and anti-angiogenic therapy.

Keywords

Angiogenesis; HUVECs; Indazole derivative; Rheumatoid arthritis; VEGFR2.

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