2. Academic Validation
  3. Identification of Pyrido[3,4-d]pyrimidine derivatives as RIPK3-Mediated necroptosis inhibitors

Identification of Pyrido[3,4-d]pyrimidine derivatives as RIPK3-Mediated necroptosis inhibitors

  • Eur J Med Chem. 2023 Nov 5:259:115635. doi: 10.1016/j.ejmech.2023.115635.
Namkyoung Kim 1,  Chan-Jung Park 1,  Younghoon Kim 1,  SeongShick Ryu 1,  Hanna Cho 2,  Yunju Nam 1,  Myeonggil Han 3,  Jeon-Soo Shin 3,  Taebo Sim 4
Affiliations

Affiliations

  • 1 KU-KIST Graduate School of Converging Science and Technology, Korea University, 145 Anam-ro, Seongbuk-gu, Seoul, 02841, Republic of Korea; Severance Biomedical Science Institute, Graduate School of Medicinal Science, Brain Korea 21 Project, Yonsei University College of Medicine, 50, Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea.
  • 2 Severance Biomedical Science Institute, Graduate School of Medicinal Science, Brain Korea 21 Project, Yonsei University College of Medicine, 50, Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea.
  • 3 Department of Microbiology, Yonsei University College of Medicine, Seoul, South Korea.
  • 4 KU-KIST Graduate School of Converging Science and Technology, Korea University, 145 Anam-ro, Seongbuk-gu, Seoul, 02841, Republic of Korea; Severance Biomedical Science Institute, Graduate School of Medicinal Science, Brain Korea 21 Project, Yonsei University College of Medicine, 50, Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea. Electronic address: [email protected].
PMID: 37494773 DOI: 10.1016/j.ejmech.2023.115635
Abstract

Necroptosis executed by RIPK3-mediated phosphorylation of MLKL is a programmed necrotic cell death and implicated with various diseases such as sterile inflammation. We designed and synthesized pyrido[3,4-d]pyrimidine derivatives as novel Necroptosis inhibitors capable of suppressing the phosphorylation of MLKL. Our SAR studies reveal that 20 possesses comparable inhibitory activity against RIPK3-mediated pMLKL in HT-29 cells relative to GSK872 (2), a representative selective RIPK3 Inhibitor. Based on biochemical kinase assay results, 20 is comparable to GSK872 (2) with regard to activity against RIPK3 and less potent against RIPK1 than GSK872, indicating selectivity of 20 towards RIPK3 over RIPK1 is higher than that of GSK872. In HT-29 cells, 20 inhibits Necroptosis via MLKL oligomerization impediment. Moreover, 20 suppresses migration and invasion of AsPC-1 cells by Necroptosis induced- CXCL5 secretion downregulation. Significantly, 20 could relieve the TNFα-induced systemic inflammatory response syndrome in vivo. Taken together, this study would provide a useful insight into the design of novel Necroptosis inhibitors possessing RIPK3-mediated pMLKL inhibitory activity.

Keywords

RIPK3; RIPK3 inhibitor; necroptosis; pyrido[3,4-d]pyrimidine.

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