Our team has recently developed a new Screening Compound Set of over 1,900 structurally diverse screening compounds capable of binding covalently to tyrosine residues in target proteins. These covalently binding molecules were selected from the Life Chemicals HTS Compound Collection based on a combination of specific structural fragments (functional groups or “warheads”) that were reported to form covalent bonds with a tyrosine residue in binding sites of proteins [3-7] and drug-like filters.
All potential tyrosine covalent inhibitors, also added to the main Covalent ScreeningLibrary, bear the following promising tyrosine-focused electrophilic warheads:
- sulfonyl derivatives and sulfonates
- nitriles
- alpha-ketoamides
- cyclic imines
- alkyl halides and halomethyl ketones
- cyanoacrylamides
- activated vinyls
- phosphonates
- others
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.
Figure 1. Covalent warhead distribution for compounds in the Tyrosine-focused Covalent Inhibitor Set
Background information
Recent advancements in SuFEx chemical biology have facilitated the rational design of irreversible inhibitors and chemical probes that target tyrosine residues [1]. Chemoproteomic studies employing sulfonyl fluoride-containing probes have revealed tyrosine as a primary target for these electrophiles across the proteome. For instance, treating Jurkat cells with the purine nucleotide affinity probe FSBA identified numerous labeled sites, predominantly tyrosine residues. Proteomics experiments utilizing probes and cross-referencing with structural data from the Protein Data Bank have shown that reactive tyrosine residues near protein binding sites are often close to basic amino acids (Lys, Arg, His). This proximity increases the reactivity of tyrosine by creating an electropositive field, thereby lowering its pKa [2]. Additionally, researchers revealed some promising activity of dichlorotriazines which can selectively label a low molecular weight protein using an in-gel fluorescence assay [3].
Representative compounds from the Tyrosine-focused Covalent Inhibitor Library
References:
- Narayanan, A.; Jones, L. H. Sulfonyl Fluorides as Privileged Warheads in Chemical Biology. Chem. Sci. 2015, 6, 2650–2659.
- Pahari, S.; Sun, L.; Alexov, E. PKAD: A Database of Experimentally Measured pKa Values of Ionizable Groups in Proteins. Database (Oxford) 2019, 2019, baz024.
- Crawford, L. A.; Weerapana, E. A Tyrosine-Reactive Irreversible Inhibitor for Glutathione S-Transferase Pi (GSTP1). Mol. BioSyst. 2016, 12 (6), 1768–1771.
- Lyn H. Jones: Chapter Four. Design of next-generation covalent inhibitors: Targeting residues beyond cysteine. Annual Reports in Medicinal Chemistry, Academic Press, vol. 56, 2021, pages 95-134.
- Qiao, H., Xia, M., Cheng, Y. et al. Tyrosine-targeted covalent inhibition of a tRNA synthetase aided by zinc ion. Commun Biol 6, 107 (2023). https://doi.org/10.1038/s42003-023-04517-7.
- Luca Gambini, Carlo Baggio, Parima Udompholkul, Jennifer Jossart, Ahmed F. Salem, J. Jefferson P. Perry, and Maurizio Pellecchia. Journal of Medicinal Chemistry 2019 62 (11), 5616-5627. DOI: 10.1021/acs.jmedchem.9b00561.
- Wang S, Hadisurya M, Tao WA, Dykhuizen E, Krusemark C. Covalent Protein Inhibitors via Tyrosine Conjugation with Cyclic Imine Mannich Electrophiles. ChemRxiv. 2022; doi: 10.26434/chemrxiv-2022-tvgn1.