1,3,5-Triazine as a Modular Scaffold for Covalent Inhibitors with Streamlined Target Identification
- 4 February 2013
- journal article
- Published by American Chemical Society (ACS) in Journal of the American Chemical Society
- Vol. 135 (7), 2497-2500
- https://doi.org/10.1021/ja400427e
Abstract
Small-molecule inhibitors can accelerate the functional annotation and validate the therapeutic potential of proteins implicated in disease. Phenotypic screens provide an effective platform to identify such pharmacological agents but are often hindered by challenges associated with target identification. For many protein targets, these bottlenecks can be overcome by incorporating electrophiles into small molecules to covalently trap interactions in vivo and by employing bioorthogonal handles to enrich the protein targets directly from a complex proteome. Here we present the trifunctionalized 1,3,5-triazine as an ideal modular scaffold for generating libraries of irreversible inhibitors with diverse target specificities. A divergent synthetic scheme was developed to derivatize the triazine with an electrophile for covalent modification of target proteins, an alkyne as a click-chemistry handle for target identification, and a diversity element to direct the compounds toward distinct subsets of the proteome. We specifically targeted our initial library toward cysteine-mediated protein activities through incorporation of thiol-specific electrophiles. From this initial screen we identified two compounds, RB-2-cb and RB-11-ca, which are cell permeable and highly selective covalent modifiers for Cys239 of β-tubulin (TUBB) and Cys53 of protein disulfide isomerase (PDI) respectively. These compounds demonstrate in vitro and cellular potencies that are comparable to currently available modulators of tubulin polymerization and PDI activity. Our studies demonstrate the versatility of the triazine as a modular scaffold to generate potent and selective covalent modifiers of diverse protein families for chemical genetics applications.Keywords
This publication has 30 references indexed in Scilit:
- Diverse Functional Roles of Reactive CysteinesACS Chemical Biology, 2012
- Irreversible Protein Kinase Inhibitors: Balancing the Benefits and RisksJournal of Medicinal Chemistry, 2012
- Quantitative reactivity profiling predicts functional cysteines in proteomesNature, 2010
- Disparate proteome reactivity profiles of carbon electrophilesNature Chemical Biology, 2008
- Functional Interrogation of the Kinome Using Nucleotide Acyl PhosphatesBiochemistry, 2006
- Global mapping of pharmacological spaceNature Biotechnology, 2006
- Chemical GeneticsChemical Reviews, 2006
- A Stepwise Huisgen Cycloaddition Process: Copper(I)-Catalyzed Regioselective “Ligation” of Azides and Terminal AlkynesAngewandte Chemie-International Edition, 2002
- Functional Consequences of Cysteine Modification in the Ligand Binding Sites of Peroxisome Proliferator Activated Receptors by GW9662Biochemistry, 2002
- Modification of Cysteine Residues by Alkylation. A Tool in Peptide Mapping and Protein IdentificationAnalytical Chemistry, 1998