Insight from Linker Investigations: Discovery of a Novel Phenylbenzothiazole Necroptosis Inhibitor Targeting Receptor-Interacting Protein Kinase 1 (RIPK1) from a Phenoxybenzothiazole Compound with Dual RIPK1/3 Targeting Activity

  • J Med Chem. 2023 Nov 2. doi: 10.1021/acs.jmedchem.3c01351.
Jing-Jie Fang  1 ,  Hou-Zong Yao  2 ,  Chunlin Zhuang  3  4 ,  Fen-Er Chen  1  5  3  4
Affiliations
  • 1. Institute of Pharmaceutical Science and Technology, Zhejiang University of Technology, Hangzhou 310014, China.
  • 2. College of Life Sciences, Jiangxi Normal University, Nanchang 330022, China.
  • 3. Engineering Center of Catalysis and Synthesis for Chiral Molecules, Department of Chemistry, Fudan University, Shanghai 200433, China.
  • 4. Shanghai Engineering Center of Industrial Asymmetric Catalysis for Chiral Drugs, Shanghai 200433, China.
  • 5. College of Chemistry and Chemical Engineering, Jiangxi Normal University, Nanchang 330022, China.
PMID: 37917221 DOI: 10.1021/acs.jmedchem.3c01351
Abstract

Necroptosis, a regulated cell death form, is a critical contributor in various inflammatory diseases. We previously identified a phenoxybenzothiazole SZM-610 as a RIPK1 and RIPK3 Necroptosis inhibitor. We conducted extensive studies to investigate different chemical components' effects on antinecroptosis activity and RIPK1/3 activity. This study focused on replacing the linker in phenoxybenzothiazoles to assess its impact. Remarkably, compound 10, bearing a novel 3,2'-phenylbenzothiazole scaffold, exhibited fourfold more potent nanomolar activity than SZM-610. Unlike SZM-610, this compound inhibited RIPK1 (Kd = 17 nM) and eliminated RIPK3 inhibition at 5000 nM. Various linkages confirmed the 3,2'-phenylbenzothiazole superior potency. Moreover, this compound specifically inhibited Necroptosis by inhibiting RIPK1, RIPK3, and MLKL phosphorylation. In a TNF-induced inflammatory model, it dose-dependently (1.25-5 mg/kg) protected mice from hypothermia and death, surpassing SZM-610's effectiveness. These findings highlight 3,2'-phenylbenzothiazole as a promising lead structure for developing drugs targeting necroptosis-related diseases.

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