Advances in covalent kinase inhibitors

Citations Over TimeTop 1% of 2020 papers

Abstract

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.

Related Papers

• → A comparison between theoretical and experimental models of electrophilicity and nucleophilicity(2008)74 cited
• → A quantitative approach to polar organic reactivity(2015)63 cited
• → Electrophilicity–Nucleophilicity Scale Also in the Gas Phase(2006)20 cited
• → Further reactions of phenyldimethylsilyllithium with N,N-dimethylamides(2002)2 cited
• → Construction and Application of Reference Scales for the Characterization of Cationic Electrophiles and Neutral Nucleophiles(2003)1 cited