Covalent binding design strategy: A prospective method for discovery of potent targeted anticancer agents

Eur J Med Chem. 2017 Dec 15;142:493-505. doi: 10.1016/j.ejmech.2017.09.024. Epub 2017 Sep 20.


Cancer remains the most serious disease that threatens human health. Molecularly targeted cancer therapies, specifically small-molecule protein kinase inhibitors, form an important part of cancer therapy. Targeted covalent modification represents a proven approach to drug discovery with the recent FDA approvals of afatanib, ibrutinib, and osimertinib agents, which were designed to undergo an irreversible hetero-Michael addition reaction with a unique cysteine residue of a specific protein. Covalent inhibitors possess numerous advantages, including increased biochemical efficacy, longer duration of action, the high potential for improved therapeutic index due to lower effective dose, and the potential to inhibit certain drug resistance mechanisms. In this regard, the novel targeted anticancer agents whose activity is presumably dependent upon a hetero-Michael addition reaction with thiols are summarized in this article.

Keywords: Cancer; Covalent; Design; Inhibitors; Kinase.

Publication types

  • Review

MeSH terms

  • Animals
  • Antineoplastic Agents / chemistry*
  • Antineoplastic Agents / pharmacology*
  • Drug Design*
  • Humans
  • Models, Molecular
  • Molecular Targeted Therapy
  • Neoplasms / drug therapy*
  • Neoplasms / metabolism
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / pharmacology*


  • Antineoplastic Agents
  • Protein Kinase Inhibitors