ArticleBioorganic & medicinal chemistry2017
Structure-guided development of covalent TAK1 inhibitors.
Article in Bioorganic & medicinal chemistry, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed.
- Chemical genetics reveals Leishmania KKT2 and CRK9 kinase activity is required for cell cycle progression.PLoS pathogens · 2026Article
- Discovery and Characterization of Cell-Permeable Inhibitors ofACS infectious diseases · 2025Article
- Biological and Medicinal Properties ofInternational journal of molecular sciences · 2025Review
- Canonical and noncanonical Wnt signaling: Multilayered mediators, signaling mechanisms and major signaling crosstalk.Genes & diseases · 2024Review
- Proteome-Wide Profiling of the Covalent-Druggable Cysteines with a Structure-Based Deep Graph Learning Network.Research (Washington, D.C.) · 2022Article
- The versatile utility of cysteine as a target for cancer treatment.Frontiers in oncology · 2022Review
- Assessing reversible and irreversible binding effects of kinase covalent inhibitors through ADP-Glo assays.STAR protocols · 2021Article
- Inhibitors of Cyclin-Dependent Kinases: Types and Their Mechanism of Action.International journal of molecular sciences · 2021Review
- Structure-Based Design of a Potent and Selective Covalent Inhibitor for SRC Kinase That Targets a P-Loop Cysteine.Journal of medicinal chemistry · 2020Article
- Structure and Characterization of a Covalent Inhibitor of Src Kinase.Frontiers in molecular biosciences · 2020Article
- Leveraging Compound Promiscuity to Identify Targetable Cysteines within the Kinome.Cell chemical biology · 2019Article
- Development of a Selective CDK7 Covalent Inhibitor Reveals Predominant Cell-Cycle Phenotype.Cell chemical biology · 2019Article
- A multitargeted probe-based strategy to identify signaling vulnerabilities in cancers.The Journal of biological chemistry · 2019Article
- Pleiotropic Effects of PPARD Accelerate Colorectal Tumorigenesis, Progression, and Invasion.Cancer research · 2019Article
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Authors and funding
16 authors.
Funding
Abstract
TAK1 (transforming growth factor-β-activated kinase 1) is an essential intracellular mediator of cytokine and growth factor signaling and a potential therapeutic target for the treatment of immune diseases and cancer. Herein we report development of a series of 2,4-disubstituted pyrimidine covalent TAK1 inhibitors that target Cys174, a residue immediately adjacent to the 'DFG-motif' of the kinase activation loop. Co-crystal structures of TAK1 with candidate compounds enabled iterative rounds of structure-based design and biological testing to arrive at optimized compounds. Lead compounds such as 2 and 10 showed greater than 10-fold biochemical selectivity for TAK1 over the closely related kinases MEK1 and ERK1 which possess an equivalently positioned cysteine residue. These compounds are smaller, more easily synthesized, and exhibit a different spectrum of kinase selectivity relative to previously reported macrocyclic natural product TAK1 inhibitors such as 5Z-7-oxozeanol.
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Registered trials
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