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Covalent Fragment Screening Using the Quantitative Irreversible Tethering Assay
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Chemical Proteomics-Guided Discovery of Covalent Ligands for Cancer Proteins

Xiaoyu Zhang1, Benjamin F Cravatt2

  • 1Department of Chemistry, Northwestern University, Evanston, IL 60208, USA.

Annual Review of Cancer Biology
|September 19, 2025
PubMed

Insights

Innovations in chemical proteomics and covalent chemistry are enabling the development of novel small molecule drugs targeting previously undruggable cancer proteins. These approaches offer new ways to perturb protein functions and advance cancer treatment.

Area of Science:

  • Biochemistry
  • Chemical Biology
  • Oncology

Background:

  • Genomic advances have improved understanding of cancer pathways.
  • Targeting oncogenic proteins with conventional drugs remains difficult.

Purpose of the Study:

  • To discuss the integration of chemical proteomics and covalent chemistry for cancer drug discovery.
  • To explore how these methods identify and advance novel small molecule cancer therapeutics.

Main Methods:

  • Utilizing innovations in chemical proteomics.
  • Applying principles of covalent chemistry.
  • Conducting mechanistic studies on small molecule interactions with proteins.

Main Results:

  • Covalent compounds were identified as first-in-class small molecules targeting cancer proteins.
  • Mechanistic studies revealed diverse perturbations of protein functions by covalent compounds.
  • These perturbations include remodeling of protein-protein and protein-RNA complexes and altered post-translational modifications.

Conclusions:

  • Chemical proteomics and covalent chemistry enable targeting of previously inaccessible cancer pathways.
  • Further technical development is needed to fully realize the druggability of the cancer proteome.

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