Advances in covalent kinase inhibitors

Ayah Abdeldayem, Yasir S. Raouf, Stefan N. Constantinescu, Richard Moriggl, Patrick T. Gunning

Research output: Contribution to journalReview articlepeer-review

160 Citations (Scopus)


Over the past decade, covalent kinase inhibitors (CKI) have seen a resurgence in drug discovery. Covalency affords a unique set of advantages as well as challenges relative to their non-covalent counterpart. After reversible protein target recognition and binding, covalent inhibitors irreversibly modify a proximal nucleophilic residue on the protein via reaction with an electrophile. To date, the acrylamide group remains the predominantly employed electrophile in CKI development, with its incorporation in the majority of clinical candidates and FDA approved covalent therapies. Nonetheless, in recent years considerable efforts have ensued to characterize alternative electrophiles that exhibit irreversible or reversibly covalent binding mechanisms towards cysteine thiols and other amino acids. This review article provides a comprehensive overview of CKIs reported in the literature over a decade period, 2007-2018. Emphasis is placed on the rationale behind warhead choice, optimization approach, and inhibitor design. Current FDA approved CKIs are also highlighted, in addition to a detailed analysis of the common trends and themes observed within the listed data set.

Original languageEnglish
Pages (from-to)2617-2687
Number of pages71
JournalChemical Society Reviews
Issue number9
Publication statusPublished - May 7 2020
Externally publishedYes

ASJC Scopus subject areas

  • General Chemistry


Dive into the research topics of 'Advances in covalent kinase inhibitors'. Together they form a unique fingerprint.

Cite this