Continued interest and research efforts has led to over 33 covalent inhibitors receiving regulatory approval as therapeutics (Supplementary table and Figure and). While mostly dominated by α,β unsaturated carbonyls, other warheads such as boronic acids and ester, αketoamides, nitriles and butynamides have also been used in USFDA approved drugs (Figure ). Cysteine continues to be the target residue of choice, with only a handful of approved covalent inhibitors targeting serine, threonine and lysine residues (Figure ). A majority of the approved covalent therapeutics are utilized in the treatment of cancer (~66%) followed by autoimmune diseases (such as rheumatoid arthritis and multiple sclerosis) and antivirals (SARS Cov-2 and hepatitis C) (Figure ). Approved covalent inhibitors are spread across a range of protein targets with the highest number for EGFR followed by BTK (Figure ). Notable among the approved covalent therapeutics is BTK inhibitor Ibrutinib (Imbruvica). Used to treat multiple types of myelomas as well as other indications, it was ranked in the top 20 drugs for global sales from 2019-2021 reaching $9.8 billion in global sales in 2021 which is a testament to the potential of covalent inhibitors as profitable drugs. 296, 297 Three companies have each launched 3 covalent inhibitor therapeutics in the past 20 years: Takeda, AstraZeneca and Pfizer. Two of Takeda's drugs, Bortezomib (Velcade) and Ixazomib (Ninlaro) 299 , use boronic acid warheads that act on proteosomes to treat mantle cell lymphoma and multiple myeloma, respectively. The third Takeda covalent inhibitor, Mobocertinib (Exkivity), uses an acrylamide warhead to treat non-small cell lung cancer (NSCLC) through action at EGFR. 300 Two of AstraZeneca's covalent inhibitors use α,β-unsaturated amides as warheads: Acalabrutinib (Calquence) has an alkyne that targets BTK and is used to treat various types of lymphomas 110 , while Osimertinib (Tagrisso) uses an acrylamide warhead to interact with EGFR creating a viable therapeutic for NSCLC. Meanwhile both of Pfizer's drugs, Tofactinib (Xeljanz) and Nirmatrelvir (Paxlovid) utilize nitriles as warheads.