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Specific Covalent Inhibitor Fragment Library

Compounds bearing specific reactive moieties such as acrylamide, vinulsulfone, and vinylsulfonamide groups can be used as potent pharmaceutical agents, and their presence could potentially improve the drug-like properties of potential drug candidates.1

Recent interest in these compounds is associated with the design of covalent inhibitors of cysteine proteases2 and protein kinases3 that represent promising drug targets for the treatment of thrombosis and various cancers. While most enzyme inhibitors described to date are the compounds that bind with a target reversibly, covalent modifiers act irreversibly through the formation of covalent bond(s) with nucleophilic residues in the binding site. A good example is the recent identification of acrylamide derivatives capable of inhibiting the clinically relevant EGFR kinase mutant forms.4

Several inhibitors capable of covalent binding with their targets recently came into the pharmacological market. Examples of the two marketed drugs used in the chemotherapy of different forms of cancer are given in Figure 1.5,6 Both compounds contain activated double bonds that readily undergo reaction with amine or thiol functionalities (usually those of cysteine residue).

Examples of approved drugs capable to inhibit protein kinases irreversibly 

Figure 1. Examples of approved drugs capable of inhibiting human protein kinases irreversibly.

In line with a growing interest and widespread use of fragment-based drug discovery (FBDD), Life Chemicals designed its Specific Covalent Inhibitor Fragment Library. Around 600 structurally diverse compounds bearing carbon-carbon double bonds activated by either carbonyl or sulfo groups were extracted from the HTS Compound Collection applying the modified Ro3 criteria. In-house developed medicinal chemistry filters were employed to remove undesired chemotypes.

Representative compounds from the Specific Covalent Inhibitor Fragment Library


  1. Wu KD, Chen GS, Liu JR, Hsieh CE, Chern JW. Acrylamide Functional Group Incorporation Improves Drug-like Properties: An Example with EGFR Inhibitors. ACS Med Chem Lett. 2018 Dec 6;10(1):22-26.
  2. Palmer JT, Rasnick D, Klaus JL, Brömme D. Vinyl sulfones as mechanism-based cysteine protease inhibitors. J Med Chem. 1995 Aug 18;38(17):3193-6.
  3. Liu Q, Sabnis Y, Zhao Z, Zhang T, Buhrlage SJ, Jones LH, Gray NS. Developing irreversible inhibitors of the protein kinase cysteinome. Chem Biol. 2013 Feb 21;20(2):146-59.
  4. Amaral DN, Lategahn J, Fokoue HH, da Silva EMB, Sant'Anna CMR, Rauh D, Barreiro EJ, Laufer S, Lima LM. A novel scaffold for EGFR inhibition: Introducing N-(3-(3-phenylureido)quinoxalin-6-yl) acrylamide derivatives. Sci Rep. 2019 Jan 9;9(1):14.
  5. Greig SL. Osimertinib: First Global Approval. Drugs. 2016 Feb;76(2):263-73.
  6. Brown JR. Ibrutinib (PCI-32765), the first BTK (Bruton's tyrosine kinase) inhibitor in clinical trials. Curr Hematol Malig Rep. 2013 Mar;8(1):1-6.
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