2. Academic Validation
  3. Development of Potent and Selective CK1α Molecular Glue Degraders

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

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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