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.
Covalent Kinase Inhibitors (CKIs) have generated much excitement and gained traction as an effective strategy for small molecule interrogation of the kinome. CKI’s are important therapeutic agents which ideally exhibit rapid target engagement, improved potency and selectivity. Most recently, efforts to fine tune electrophilic reactivity has facilitated improved clinical efficacy and patient outcomes. Due to the ubiquitous role played by kinases in disease, a comprehensive review of CKIs, an increasingly popular drug modality that offers promise of improving kinase-selectivity profiles, would be of great interest to the fields of medicinal chemistry and chemical biology.
This comprehensive review details the last 10-years of kinase-targeting covalent inhibitors, consolidating all published inhibitors within this period. It provides a focus on electrophilic warhead development, scaffold design, metabolic stability and pharmacodynamics. In addition, to achieve further insight into covalent strategies, the review includes a detailed data analysis section regarding the chemical and physical properties of CKIs. This illuminate the trends which underpin their positive and negative attributes. This analysis may inform and accelerate current and future programs utilizing a covalent approach in drug discovery or chemical biologyYasir Raouf
Chem Soc Rev 2020 May 30;49(9):2617-2687. Epub 2020 Mar 30.
Department of Chemical & Physical Sciences, University of Toronto, 3359 Mississauga Road, Mississauga, ON L5L 1C6, Canada.
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