Emerging and Re-emerging Warheads for Targeted Covalent Inhibitors: An Update

Development of Highly Potent and Selective Covalent FGFR4 Inhibitors Based on SNAr Electrophiles

“…Importantly, kinact is not necessarily correlated with intrinsic chemical reactivity since it is also impacted by pre-orientation to favor a low activation energy reaction trajectory and a possible activation of the electrophile by its non-covalent interactions with the target. 47,48 Since the determination covalent binding kinetics is relatively labor and resource intensive, it is common practice in the protein kinase field to perform early compound profiling by IC50 values determined under equivalent conditions while key compounds are subjected to kinetic profiling. Thus, we determined KI, kinact, and the kinact/KI values of our lead compounds 8A and 8B and reference compound BLU9931.…”

“…45,46 An underexplored approach to covalently addressing cysteines involves warheads based on electron-deficient (hetero)aromatic rings equipped with a leaving group, which can react with nucleophiles via a nucleophilic aromatic substitution (SNAr) reaction (see the mechanism in Figure 2C). 47,48 The general applicability of this approach to targeting FGFR4-C552 has been proven by Fairhurst et al, who identified fragment-like chloronitropyridine-based inhibitor 6 in a high-throughput screen (Figure 1). 30 However, this compound was not pursued further in favor of the reversiblecovalent inhibitors mentioned above.…”

Structure Activity of β-Amidomethyl Vinyl Sulfones as Covalent Inhibitors ofChikungunyansP2 Cysteine Protease with Anti-alphavirus Activity

“…7 The tunability and utility of vinyl sulfones as covalent warheads for irreversible cysteine targeting has been studied extensively. 8 Notably, 1a was remarkably selective across a wide panel of diverse cysteine proteases. 7 Furthermore, the clinical development of vinyl sulfones has been demonstrated by K777 (Figure 1A), 9 a covalent cysteine protease inhibitor that was effective in animal models of Chagas disease, schistosomiasis, hookworm infection, and cryptosporidiosis and VVD-133214, a covalent WRN helicase inhibitor that was recently advanced to clinical trials for cancers with microsatellite instability.…”