Repurposing crizotinib to target RIPK1-dependent cell death.

Area of Science:

• Biochemistry
• Pharmacology
• Immunology

Background:

• Receptor-interacting protein kinase 1 (RIPK1) is a critical regulator of cell death and inflammation, implicated in numerous inflammatory and degenerative diseases.
• RIPK1 is a promising therapeutic target, but effective pharmacological inhibitors for RIPK1-mediated cell death are lacking in clinical use.
• Repurposing existing drugs offers an expedited pathway for clinical development.

Purpose of the Study:

• To identify existing drugs that can inhibit Receptor-Interacting Protein Kinase 1 (RIPK1)-dependent cell death.
• To evaluate the therapeutic potential of identified compounds in preclinical models of inflammatory diseases.

Main Methods:

• Conducted a high-throughput drug screen utilizing a library of Food and Drug Administration (FDA)-approved compounds.
• Tested the efficacy of identified compounds in inhibiting RIPK1-dependent cell death.
• Assessed the protective effect of crizotinib against tumor necrosis factor-alpha (TNF-α)-induced death in a mouse model of systemic inflammatory response syndrome.
• Determined the direct inhibitory effect of crizotinib on RIPK1 kinase activity.

Main Results:

• Identified crizotinib as a novel inhibitor of RIPK1-dependent cell death.
• Crizotinib demonstrated efficacy in rescuing mice from TNF-α-induced death in a systemic inflammatory response syndrome model.
• Direct inhibition of RIPK1 kinase activity by crizotinib was confirmed.

Conclusions:

• Crizotinib exhibits a previously unrecognized inhibitory effect on RIPK1 kinase activity and RIPK1-dependent cell death.
• This repurposed drug holds potential for accelerating the development of therapeutics for a range of RIPK1-spectrum disorders.
• The findings support the advancement of crizotinib as a potential treatment for inflammatory and degenerative conditions driven by RIPK1 signaling.