Tofactinib is a JAK inhibitor that is used primarily for rheumatoid arthritis and Nirmatrelvir is an inhibitor of SARS-CoV-2 major protein used to treat COVID-19. Its worldwide sales were $19 billion in 2022. The third Pfizer drug is Dalomitinib (Vizimpro) using a substituted acrylamide as a warhead to serve as an EGFR inhibitor in the treatment of NSCLC. Several covalent inhibitors are currently in clinical trials (Table and Figures and). Close to half of the covalent inhibitors currently in development are in phase 3, 20% of them have been abandoned and the rest are evenly distributed across phase I and II (Figure ). An overwhelming majority of these utilize an acrylamide moiety as the warhead (Figure ) and almost all of them target cysteine residues. Similar to FDA approved covalent therapeutics, trends for covalent inhibitors currently in development indicate that cancer (~70%) continue to be the most targeted indication followed by autoimmune diseases (~15%) (Figure ). Out of the 18 covalent inhibitors currently in various stages of clinical trials, 50% and 25% target EGFR and BTK, respectively (Figure ). Other targets of covalent inhibitors in development include FGFR, JAK and CatK (Figure ). Three of those trials are for Novartis compounds. The first two, Remibrutinib and Narzartinib, use an acrylamide warhead to form a covalent bond with the target. Remibrutinib is currently in Phase III clinical trials for use in chronic uticaria through inhibiting BTK. Nazartinib is currently in Phase II clincal trials as an EGFR inhibitor for the treatment of NSCLC. The third Novartis compound, currently in stage I/II clinical studies, is Roblitinib which uses an aryl aldehyde to be a reversible covalent inhibitor of FGFR4 to serve as a treatment for hepatocellular carcinoma and solid tumors. Bristol-Myers Squibb also has multiple covalent inhibitors that act through BTK currently in the clinic. Branebrutinib has an alkyne amide as a warhead and is currently in Phase II trials as a treatment for rheumatoid arthritis. Spebrutinib is currently in Phase I trials as a treatment for large B-cell lymphoma using an acrylamide as a warhead. 308