Orally effective FDA-approved protein kinase targeted covalent inhibitors (TCIs): A 2025 update.

in Pharmacological research by Robert Roskoski

TLDR

  • A review of FDA-approved targeted covalent inhibitors for treating various human diseases, highlighting their mechanism of action and potential impact on therapy.

Abstract

Because aberrations of protein kinase activity play causal roles in several human diseases, this family of enzymes is one of the most important drug targets of the 21century. Of the 88 protein kinase antagonists that are approved by the FDA, eleven of them form irreversible covalent complexes with their target enzymes. The clinical efficacy of ibrutinib, a Bruton tyrosine kinase blocker, in the treatment of mantle cell lymphoma following its 2013 approval helped to overcome a general bias against the development of irreversible drug inhibitors. Other approved targeted covalent inhibitors include acalabrutinib and zanubrutinib, which also block Bruton tyrosine kinase. Afatinib, dacomitinib, lazertinib, mobocertinib, and osimertinib inhibit members of the epidermal growth factor receptor family (ErbB1/2/3/4) and are used in the treatment of non-small cell lung cancers. Neratinib inhibits ErbB2 and is used in the management of ErbB2/HER2-positive breast cancer. Futibatinib blocks the fibroblast growth factor receptor family and is prescribed for the treatment of cholangiocarcinoma while ritlecitinib, which inhibits JAK3, is used in the management of alopecia areata. The eleven drugs considered in this review have a common mechanism of action involving the addition of a protein cysteine thiolate anion (proteinS:) to an acrylamide or an acrylamide-like derivative producing a thioether. The development of targeted covalent inhibitors is gaining acceptance as a valuable component of the medicinal chemist's toolbox and has made a significant impact on the development of protein kinase antagonists and receptor modulators.

Overview

  • The study focuses on the protein kinase family of enzymes, which is a vital target for discovering novel therapeutics to treat various human diseases.
  • Eleven approved protein kinase antagonists form irreversible covalent complexes with their target enzymes, and these drugs have shown clinical efficacy in treating various types of cancer.
  • The primary objective of the study is to review the development of targeted covalent inhibitors and their potential impact on the treatment of human diseases.

Comparative Analysis & Findings

  • Eleven FDA-approved targeted covalent inhibitors were identified, including ibrutinib, acalabrutinib, zanubrutinib, afatinib, dacomitinib, lazertinib, mobocertinib, osimertinib, neratinib, futibatinib, and ritlecitinib.
  • These drugs have been approved for the treatment of various types of cancer, such as mantle cell lymphoma, non-small cell lung cancer, breast cancer, and cholangiocarcinoma.
  • A common mechanism of action among these drugs involves the formation of a thioether bond between the enzyme and the inhibitor, resulting in irreversible binding.

Implications and Future Directions

  • The development of targeted covalent inhibitors has expanded the therapeutic possibilities for protein kinase antagonists and receptor modulators.
  • Future studies may focus on optimizing the design of these inhibitors to improve efficacy, reducing side effects, and exploring their applicability for treating other diseases.
  • Targeted covalent inhibitors show promise for treating various human diseases, and continued research in this area may lead to the discovery of novel therapeutic strategies.
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