A5091890970- Crystallization and Solubility Studies
- X-ray Diffraction in Crystallography
- Neuropeptides and Animal Physiology
- Peptidase Inhibition and Analysis
- Diabetes Treatment and Management
- Cancer-related Molecular Pathways
- Cancer, Hypoxia, and Metabolism
- Ubiquitin and proteasome pathways
- RNA modifications and cancer
- Cancer, Lipids, and Metabolism
- Crystallography and molecular interactions
- Protein Degradation and Inhibitors
- Advanced Chemical Physics Studies
- RNA and protein synthesis mechanisms
- Pharmacological Receptor Mechanisms and Effects
- Receptor Mechanisms and Signaling
- RNA Research and Splicing
- Metabolism, Diabetes, and Cancer
- Spectroscopy and Quantum Chemical Studies
- Lipid metabolism and biosynthesis
- Analytical Chemistry and Chromatography
- Chronic Lymphocytic Leukemia Research
- Neuroscience and Neuropharmacology Research
- Chemical Thermodynamics and Molecular Structure
- Molecular spectroscopy and chirality
Takeda (Japan)
2011-2023
Takeda (United States)
2010
Osaka University of Pharmaceutical Sciences
1988-1991
Osaka University
1987
Research Article16 May 2018Open Access Source DataTransparent process Anti-tumor efficacy of a novel CLK inhibitor via targeting RNA splicing and MYC-dependent vulnerability Kenichi Iwai Oncology Drug Discovery Unit, Takeda Pharmaceutical Company, Limited, Fujisawa, Japan Search for more papers by this author Masahiro Yaguchi Kazuho Nishimura Yukiko Yamamoto Toshiya Tamura Daisuke Nakata Ryo Dairiki Yoichi Kawakita Mizojiri Yoshiteru Ito Moriteru Asano Hironobu Maezaki Yusuke Nakayama...
Cyclin-dependent kinase 12 (CDK12) plays a key role in the coordination of transcription with elongation and mRNA processing. CDK12 mutations found tumors inhibition sensitize cancer cells to DNA-damaging reagents DNA-repair inhibitors. This suggests that inhibitors are potential therapeutics for may cause synthetic lethality. Here, we report discovery 3-benzyl-1-(trans-4-((5-cyanopyridin-2-yl)amino)cyclohexyl)-1-arylurea derivatives as novel selective Structure–activity relationship studies...
Inhibition of dipeptidyl peptidase IV (DPP-4) is an exciting new approach for the treatment diabetes. To date there has been no DPP-4 chemotype possessing a carboxy group that progressed into clinical trials. Originating from discovery structurally novel quinoline derivative 1, we designed pyridine derivatives containing group. In our design, interacted with targeted amino acid residues around catalytic region and thereby increased inhibitory activity. After further optimization, identified...
Intermolecular interactions in CH/π systems have been studied by PCILO and ab initio MO methods to elucidate the origin of attractive interactions. In calculations, van der Waals molecules CH4+ C2Hn(n= 2 or 4) were more stable than that C2H6, most arrangement was such carbon atom methane is shifted from C2 axis perpendicular C–C–H plane ethene. Ab results supported this conclusion showed also main contributions come electrostatic charge-transfer effects. These electrostatic-potential maps C2H4 C2H6.
Brr2 is an RNA helicase belonging to the Ski2-like subfamily and essential component of spliceosome. catalyzes ATP-dependent unwinding U4/U6 duplex, which a critical step for spliceosomal activation. An HTS campaign using RNA-dependent ATPase assay initial SAR study identified two different inhibitors, 3 12. Cocrystal structures revealed binds unexpected allosteric site between C-terminal N-terminal cassettes, while 12 RNA-binding inside cassette. Selectivity profiling indicated inhibitor...
Targeted protein degradation via the ubiquitin-proteasome system has emerged as one of most promising drug discovery modalities. Autophagy, another intracellular system, can target a wide range nonproteinous substrates well proteins, but its application to targeted is still in infancy. Our previous work revealed relationship between guanine modification cysteine residues on proteins and selective autophagy, resulting first autophagy-based degraders, autophagy-targeted chimeras (AUTACs)....
We initiated our structure-activity relationship (SAR) studies for selective ACC1 inhibitors from 1a as a lead compound. SAR of bicyclic scaffolds revealed many potent and represented by 1f; however most them had physicochemical issues, particularly low aqueous solubility CYP inhibition. To address these two issues improve the druglikeness this chemical series, we converted scaffold into monocyclic framework. Ultimately, us to discover novel derivative 1q inhibitor, which showed highly...
Phenotypic screening is gaining attention as a powerful method for identifying compounds that regulate cellular phenotypes of interest through novel mechanisms action. Recently, new modality compounds, called molecular glues, which can induce the degradation target proteins by forming ternary complexes E3 ligases, has emerged from phenotypic screening. In this study, using global proteomic analysis, we identified Cyclin K degrader, T4, was previously discovered alternative polyadenylation...
A structure–activity relationship (SAR) study towards novel ACC1-selective inhibitors was carried out by modifying the molecular length of linker in biaryl derivative 1 g, an ACC1/2 dual inhibitor. Ultimately, this leads us to discover phenoxybenzyloxy 1i as a potent Further chemical modification scaffold improve cellular potency well physicochemical and pharmacokinetic (PK) properties produced N-2-(pyridin-2-ylethyl)acetamide 1n, which showed highly inhibition sufficient PK profile for...