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  3. Design, Optimization, and Development of RIPK1 Degraders with Improved Pharmacokinetic and Pharmacodynamic Properties

Design, Optimization, and Development of RIPK1 Degraders with Improved Pharmacokinetic and Pharmacodynamic Properties

  • J Med Chem. 2025 Nov 13;68(21):22246-22263. doi: 10.1021/acs.jmedchem.5c00773.
Dong Lu 1,  Xin Yu 1 2,  Hanfeng Lin 1 2,  Ran Cheng 1 2,  Bin Yang 1 2,  Min Zhang 1 2,  Jingjing Chen 1 2,  Feng Li 3 4,  Xiaoli Qi 1 2,  Jin Wang 1 2 5
Affiliations

Affiliations

  • 1 Verna and Marrs McLean Department of Biochemistry and Molecular Pharmacology, Baylor College of Medicine, Houston, Texas 77030, United States.
  • 2 Center for NextGen Therapeutics, Baylor College of Medicine, Houston, Texas 77030, United States.
  • 3 Department of Pathology, Baylor College of Medicine, Houston, Texas 77030, United States.
  • 4 Center for Drug Discovery, Baylor College of Medicine, Houston, Texas 77030, United States.
  • 5 Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, United States.
PMID: 41134612 DOI: 10.1021/acs.jmedchem.5c00773
Abstract

Pharmacological degradation of receptor-interacting protein kinase 1 (RIPK1) offers a compelling therapeutic strategy to overcome its scaffolding role in tumor resistance and enhance the efficacy of immune checkpoint blockade (ICB) therapies. In this study, we report the discovery of a novel RIPK1 degrader, LD5097 (24b), developed through systematic optimization of its precursor compound, LD4172─specifically refining the linker, RIPK1 warhead exit vector, and VHL ligand components. LD5097 (24b) exhibits potent and selective RIPK1 degradation, triggering rapid and efficient downregulation of RIPK1 and significantly enhancing TNFα-mediated Apoptosis in Jurkat cells. Compared with LD4172, LD5097 (24b) demonstrates markedly improved metabolic stability and pharmacokinetic properties. In vivo, a single dose of LD5097 (24b) induced over 70% RIPK1 degradation in Jurkat xenograft tumors in mice within 6 h. These results position LD5097 (24b) as a promising therapeutic candidate, combining potent biological activity with favorable drug-like properties, and offering strong potential for application in Cancer Immunotherapy.

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