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Chemical Inactivation of the E3 Ubiquitin Ligase Cereblon by Pomalidomide-based Homo-PROTACs
Published on: May 15, 2019
Discovery and Development of First-in-Class Cereblon-Recruiting RIPK1 Degraders
Dong Lu1, Xin Yu1,2, Hanfeng Lin1,2
1Verna and Marrs McLean Department of Biochemistry and Molecular Pharmacology, Baylor College of Medicine, Houston, TX 77030.
Abstract:
Receptor-interacting protein kinase 1 (RIPK1) is a critical regulator of programmed cell death and is implicated in various pathological conditions, particularly in mediating tumor resistance to immune checkpoint inhibitors (ICBs). In this study, we have pioneered the development of a novel cereblon (CRBN)-recruiting RIPK1 degrader, LD5095, through systematic optimization of linker and CRBN ligand portion. LD5095 demonstrates potent and selective RIPK1 degradation across cell lines, with rapid kinetics and sustained degradation over 72h post-washout. Functionally, RIPK1 degradation by LD5095 significantly sensitized Jurkat cells to TNFα-induced apoptosis. Furthermore, LD5095 exhibited favorable pharmacokinetics, including metabolic stability and an extended half-life. Strikingly, in vivo, a single dose of LD5095 achieved durable RIPK1 degradation in xenograft tumors over 6 days. These findings underscore the potential of LD5095 as a chemical probe for studying RIPK1 biology and a promising candidate for cancer treatment.
Insights
Researchers developed LD5095, a novel molecule that degrades Receptor-interacting protein kinase 1 (RIPK1). This compound shows promise in cancer treatment by sensitizing cells to apoptosis and enabling durable tumor degradation.
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.
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