2. Academic Validation
  3. Small-Molecule Receptor-Interacting Protein 1 (RIP1) Inhibitors as Therapeutic Agents for Multifaceted Diseases: Current Medicinal Chemistry Insights and Emerging Opportunities

Small-Molecule Receptor-Interacting Protein 1 (RIP1) Inhibitors as Therapeutic Agents for Multifaceted Diseases: Current Medicinal Chemistry Insights and Emerging Opportunities

  • J Med Chem. 2022 Nov 24;65(22):14971-14999. doi: 10.1021/acs.jmedchem.2c01518.
Kunyu Shi 1,  Jifa Zhang 1 2 3,  Enda Zhou 4,  Jiaxing Wang 5,  Yuxi Wang 1 2 3
Affiliations

Affiliations

  • 1 Targeted Tracer Research and Development Laboratory, Institute of Respiratory Health, Frontiers Science Center for Disease-related Molecular Network, Joint Research Institution of Altitude Health, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, 610041 Sichuan, China.
  • 2 Precision Medicine Key Laboratory of Sichuan Province & Precision Medicine Research Center, West China Hospital, Sichuan University, Chengdu, 610041 Sichuan, China.
  • 3 Tianfu Jincheng Laboratory, Chengdu, 610041 Sichuan, China.
  • 4 West China School of Pharmacy, Sichuan University, Chengdu, 610041 Sichuan, China.
  • 5 Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee 38163, United States.
PMID: 36346971 DOI: 10.1021/acs.jmedchem.2c01518
Abstract

As a serine/threonine protein kinase, receptor-interacting protein 1 (RIP1) plays an important role in regulating the pathways in programmed cell death. Multifaceted human diseases (e.g., autoimmune diseases, inflammatory diseases, neurodegenerative diseases, and tumors) are closely related to RIP1 kinase. Therefore, small-molecule RIP1 inhibitors with precise targeting and good penetrability have recently been used in potentially therapeutic methods, attracting extensive researcher interest. GSK2982772, developed by GlaxoSmithKline (GSK), became the world's first RIP1 inhibitor approved for clinical research in 2014. Nine clinical trials assessing GSK2982772 have been performed. The most recent direction in RIP1 inhibitor development has been focused on RIP1 small-molecule inhibitors with higher potency, selectivity, and metabolic stability. In this Perspective, considering the structure, biological functions, and disease relevance of RIP1, we summarize the recent research progress in RIP1 small-molecule inhibitor development based on different binding modalities and discuss prospective strategies for designing additional RIP1 therapeutic agents.

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