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Updated: Sep 3, 2026

Validation of a Mouse Model to Disrupt LINC Complexes in a Cell-specific Manner
Published on: December 10, 2015
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, Texas77030, United States.
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 (ICIs). 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 postwashout. 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.
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