Fig. 2. The structures of representative well-characterized electrophilic fragments identified from target-based screening strategies in recent years. (A) KRAS-G12C allele-specific covalent fragment (6H05) identified from tethering screen, which was further elaborated to compound 12.³¹ This inspired numerous groups to develop further optimized inhibitors, within which AMG510³³ and MRTX849³⁶ successfully entered clinical trials. (B) Compound 5 targets the active cysteine (C885) of HOIP.³⁷ (C) OTUB2-COV-1 targets the active cysteine (C51) of OTUB2 and NUDT7-COV-1 target C73 of NUDT7.³⁸ (D) Sulfopin targets the active cysteine of Pin1 (C113).³⁹ (E) Representative covalent fragment scaffolds target the active cysteine (C145) of SARS-COV-2 main protease (M^pro).⁴⁰.