Discovery and Development of First-in-Class Cereblon-Recruiting RIPK1 Degraders

Area of Science:

• Molecular Biology
• Pharmacology
• Oncology

Background:

• Receptor-interacting protein kinase 1 (RIPK1) regulates programmed cell death.
• RIPK1 is implicated in tumor resistance to immune checkpoint inhibitors (ICIs).

Purpose of the Study:

• To develop a novel cereblon (CRBN)-recruiting RIPK1 degrader.
• To evaluate the efficacy of the degrader in preclinical models.

Main Methods:

• Systematic optimization of linker and CRBN ligand portions.
• Assessment of RIPK1 degradation kinetics and selectivity in cell lines.
• Evaluation of sensitization to TNFα-induced apoptosis.
• Pharmacokinetic and *in vivo* xenograft studies.

Main Results:

• LD5095 achieved potent and selective RIPK1 degradation with rapid and sustained kinetics.
• RIPK1 degradation by LD5095 sensitized Jurkat cells to TNFα-induced apoptosis.
• LD5095 exhibited favorable pharmacokinetics and achieved durable *in vivo* tumor degradation.

Conclusions:

• LD5095 is a potent RIPK1 degrader with potential as a chemical probe.
• LD5095 demonstrates promise as a therapeutic candidate for cancer treatment.