In line with a growing interest and widespread use of fragment-based drug discovery (FBDD), Life Chemicals has designed its Specific Covalent Inhibitor Fragment Library of around 850 structurally diverse fragment-like molecules bearing carbon-carbon double bonds activated by either carbonyl or sulfo groups selected from the HTS Compound Collection applying the modified Rule of Three Ro3 criteria. In-house developed medicinal chemistry filters have been employed to remove undesired chemotypes.
It should be pointed out that our general Covalent Fragment Library comprises around 6,500 potential covalent modifiers with various covalent warheads aimed at covalent fragment screening projects.
The compound selection can be customized based on your requirements, cherry picking is available.
Please, contact us at orders@lifechemicals.com for any additional information and price quotations.
A pre-plated set based on this Screening Library can be found among our Pre-plated Fragment Screening Sets.
Background
Compounds bearing specific reactive moieties such as acrylamide, vinulsulfone, and vinylsulfonamide groups can be used as potent pharmaceutical agents, with their presence potentially improving the drug-like properties of prospective drug candidates [1]. Recent interest in these compounds is associated with the design of covalent inhibitors of cysteine proteases [2] and protein kinases [3] that represent attractive drug targets for the treatment of thrombosis and various cancers. While most enzyme inhibitors described to date are compounds that bind with a target reversibly, covalent modifiers act irreversibly by forming 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 already came into the pharmacological market. Examples of the two marketed drugs used in chemotherapy for different cancer forms 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).
Figure 1. Examples of approved drugs capable of inhibiting human protein kinases irreversibly.
Representative compounds from the Specific Covalent Inhibitor Fragment Library
References:
- Kathmana S.G., Statsyuk A. V. Covalent Tethering of Fragments For Covalent Probe Discovery, Medicinal Chemistry Communication 7(4) 2016. DOI:10.1039/C5MD00518C
- 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.
- 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.
- 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.
- 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.
- Greig SL. Osimertinib: First Global Approval. Drugs. 2016 Feb;76(2):263-73.
- 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.