Development of Potent and Selective CK1α Molecular Glue Degraders

  • J Med Chem. 2025 Feb 13;68(3):3180-3196. doi: 10.1021/acs.jmedchem.4c02415.
Qixiang Geng  1  2 ,  Zixuan Jiang  1  2  3 ,  Woong Sub Byun  1  2 ,  Katherine A Donovan  4  5 ,  Zhe Zhuang  1  2 ,  Fen Jiang  1  2 ,  Hannah M Jones  1  2 ,  Hlib Razumkov  1  2  3 ,  Michelle T Tang  1 ,  Roman C Sarott  1  2 ,  Eric S Fischer  4  5 ,  Steven M Corsello  1  6 ,  Stephen M Hinshaw  1  2 ,  Nathanael S Gray  1  2
Affiliations
  • 1. Department of Chemical and Systems Biology, Stanford Cancer Institute, School of Medicine Stanford University, Stanford, California 94305-6104, United States.
  • 2. Sarafan ChEM-H, Stanford, California 94305-6104, United States.
  • 3. Department of Chemistry, Stanford School of Humanities and Sciences and Department of Chemical and Systems Biology, ChEM-H, Stanford School of Medicine, Stanford University, Stanford, California 94305-6104, United States.
  • 4. Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215 United States.
  • 5. Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02215, United States.
  • 6. Department of Medicine, Stanford School of Medicine, Stanford, California 94305-6104, United States.
PMID: 39873536 DOI: 10.1021/acs.jmedchem.4c02415
Abstract

Molecular glue degraders (MGDs) are small molecules that facilitate proximity between a target protein and an E3 ubiquitin Ligase, thereby inducing target protein degradation. Glutarimide-containing compounds are MGDs that bind Cereblon (CRBN) and recruit neosubstrates. Through explorative synthesis of a glutarimide-based library, we discovered a series of molecules that induce Casein Kinase 1 alpha (CK1α) degradation. By scaffold hopping and rational modification of the chemical scaffold, we identified an imidazo[1,2-a]pyrimidine compound that induces potent and selective CK1α degradation. A structure-activity relationship study of the lead compound, QXG-6442, identified the chemical features that contribute to degradation potency and selectivity compared to Other frequently observed neosubstrates. The glutarimide library screening and structure-activity relationship medicinal chemistry approach we employed is generally useful for developing new molecular glue degraders toward new targets of interest.

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