Inhibitors Targeting RIPK1/RIPK3: Old and New Drugs

Area of Science:

• Molecular Biology
• Immunology
• Pharmacology

Background:

• Receptor-interacting protein kinase 1 (RIPK1) has a dual role: scaffolding prosurvival signals and mediating programmed cell death (apoptosis and necroptosis) via its kinase activity, often involving RIPK3.
• RIPK1's function is modulated by post-translational modifications like ubiquitylation and phosphorylation.
• RIPK1-induced cell death contributes to inflammatory and degenerative diseases by disrupting epithelial barriers and releasing damage-associated molecular patterns (DAMPs) and inflammatory mediators.

Purpose of the Study:

• To review and classify small-molecule drugs targeting RIPK1 and RIPK3 kinase activity.
• To analyze these drugs based on their pharmacodynamic binding modes (Type I, II, and III).
• To discuss the therapeutic potential of these inhibitors in preclinical models of inflammatory and degenerative diseases.

Main Methods:

• Literature review and classification of small-molecule inhibitors.
• Analysis of drug binding modes (Type I, II, III).
• Evaluation of drug efficacy in experimental disease models.

Main Results:

• Several small-molecule inhibitors targeting RIPK1 and RIPK3 have been developed.
• Drugs are categorized by their binding mode, influencing their mechanism of action.
• The review discusses the applicability and therapeutic promise of these agents in various disease contexts.

Conclusions:

• Targeting RIPK1 and RIPK3 kinase activity represents a promising therapeutic strategy for inflammatory and degenerative diseases.
• Understanding drug binding modes is crucial for optimizing therapeutic outcomes.
• Further investigation into the clinical applicability of these inhibitors is warranted.