ArticleJournal of medicinal chemistry2015
Discovery of type II inhibitors of TGFβ-activated kinase 1 (TAK1) and mitogen-activated protein kinase kinase kinase kinase 2 (MAP4K2).
Article in Journal of medicinal chemistry, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 37 papers.
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
37 citing papers in PubMed.
- NG25 Enhances Anti-Tumor Immunity inOncoTargets and therapy · 2026Article
- Review
- CTRP12 ameliorates post-myocardial infarction heart failure through down-regulation of cardiac apoptosis, oxidative stress and inflammation by influencing the TAK1-p38 MAPK/JNK pathway.Inflammation research : official journal of the European Histamine Research Society ... [et al.] · 2023Article
- Discovery of potent Plasmodium falciparum protein kinase 6 (PfPK6) inhibitors with a type II inhibitor pharmacophore.European journal of medicinal chemistry · 2023Article
- Strategies for Competitive Activity-Based Protein Profiling in Small Molecule Inhibitor Discovery and Characterization.Israel journal of chemistry · 2023Article
- Single-cell RNA sequencing in orthopedic research.Bone research · 2023Review
- Co-ordinated control of the ADP-heptose/ALPK1 signalling network by the E3 ligases TRAF6, TRAF2/c-IAP1 and LUBAC.The Biochemical journal · 2022Article
- TAK1 protein kinase activity is required for TLR signalling and cytokine production in myeloid cells.The Biochemical journal · 2022Article
- Semisynthesis of Hypothemycin Analogues Targeting the C8-C9 Diol.Journal of natural products · 2022Review
- IKKβ is required for the formation of the NLRP3 inflammasome.EMBO reports · 2021Article
- Review
- Discovery of 2,4-1ACS medicinal chemistry letters · 2021Article
- Targeting the GCK pathway: a novel and selective therapeutic strategy against RAS-mutated multiple myeloma.Blood · 2021Article
- Article
- TAK1 inhibition improves myoblast differentiation and alleviates fibrosis in a mouse model of Duchenne muscular dystrophy.Journal of cachexia, sarcopenia and muscle · 2021Article
- Synthesis and biological activity of 2-cyanoacrylamide derivatives tethered to imidazopyridine as TAK1 inhibitors.Journal of enzyme inhibition and medicinal chemistry · 2020Article
- Article
- TAK1: a potent tumour necrosis factor inhibitor for the treatment of inflammatory diseases.Open biology · 2020Review
- Regeneration of Damaged Tendon-Bone Junctions (Entheses)-TAK1 as a Potential Node Factor.International journal of molecular sciences · 2020Review
- Toll-like Receptor 4 Stimulates Gene Expression via Smad2 Linker Region Phosphorylation in Vascular Smooth Muscle Cells.ACS pharmacology & translational science · 2020Article
Corrections and comments
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Authors and funding
19 authors.
Funding
Abstract
We developed a pharmacophore model for type II inhibitors that was used to guide the construction of a library of kinase inhibitors. Kinome-wide selectivity profiling of the library resulted in the identification of a series of 4-substituted 1H-pyrrolo[2,3-b]pyridines that exhibited potent inhibitory activity against two mitogen-activated protein kinases (MAPKs), TAK1 (MAP3K7) and MAP4K2, as well as pharmacologically well interrogated kinases such as p38α (MAPK14) and ABL. Further investigation of the structure-activity relationship (SAR) resulted in the identification of potent dual TAK1 and MAP4K2 inhibitors such as 1 (NG25) and 2 as well as MAP4K2 selective inhibitors such as 16 and 17. Some of these inhibitors possess good pharmacokinetic properties that will enable their use in pharmacological studies in vivo. A 2.4 Å cocrystal structure of TAK1 in complex with 1 confirms that the activation loop of TAK1 assumes the DFG-out conformation characteristic of type II inhibitors.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.