Inhibitors Targeting RIPK1/RIPK3: Old and New Drugs

Trends Pharmacol Sci. 2020 Mar;41(3):209-224. doi: 10.1016/ Epub 2020 Feb 5.


The scaffolding function of receptor-interacting protein kinase 1 (RIPK1) regulates prosurvival signaling and inflammatory gene expression, while its kinase activity mediates both apoptosis and necroptosis; the latter involving RIPK3 kinase activity. The mutual transition between the scaffold and kinase functions of RIPK1 is regulated by (de)ubiquitylation and (de)phosphorylation. RIPK1-mediated cell death leads to disruption of epithelial barriers and/or release of damage-associated molecular patterns (DAMPs), cytokines, and chemokines, propagating inflammatory and degenerative diseases. Many drug development programs have pursued targeting RIPK1, and to a lesser extent RIPK3 kinase activity. In this review, we classify existing and novel small-molecule drugs based on their pharmacodynamic (PD) type I, II, and III binding mode. Finally, we discuss their applicability and therapeutic potential in inflammatory and degenerative experimental disease models.

Keywords: RIPK1 inhibitors; cell death; drug targeting; inflammation.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Apoptosis
  • Cell Death
  • Humans
  • Necrosis
  • Pharmaceutical Preparations*
  • Phosphorylation
  • Receptor-Interacting Protein Serine-Threonine Kinases* / metabolism


  • Pharmaceutical Preparations
  • RIPK1 protein, human
  • RIPK3 protein, human
  • Receptor-Interacting Protein Serine-Threonine Kinases