A5029180206- X-ray Diffraction in Crystallography
- Crystallization and Solubility Studies
- Microtubule and mitosis dynamics
- Cancer-related Molecular Pathways
- Vascular Tumors and Angiosarcomas
- Chronic Lymphocytic Leukemia Research
- Wnt/β-catenin signaling in development and cancer
- Cholinesterase and Neurodegenerative Diseases
- Alzheimer's disease research and treatments
- Protein Tyrosine Phosphatases
- Ubiquitin and proteasome pathways
- RNA modifications and cancer
- Synthesis and Biological Evaluation
- Polyamine Metabolism and Applications
- Genetic and rare skin diseases.
- Immune cells in cancer
- Drug Transport and Resistance Mechanisms
- Crystallography and molecular interactions
- Cancer therapeutics and mechanisms
- Synthesis and Reactivity of Heterocycles
- Computational Drug Discovery Methods
- Phosphodiesterase function and regulation
- HIV/AIDS drug development and treatment
- Cancer Treatment and Pharmacology
- Carbohydrate Chemistry and Synthesis
Takeda (Japan)
2009-2021
Takeda (United States)
2011-2020
Millennium Engineering and Integration (United States)
2011
Novartis (Switzerland)
2008
Novartis Institutes for BioMedical Research
2008
Novartis (Japan)
2000-2008
Japan Science and Technology Agency
2002
Okayama Psychiatric Medical Center
1987-1990
Azumi Hospital
1986
Abstract CDC-like kinase phosphorylation of serine/arginine-rich proteins is central to RNA splicing reactions. Yet, the genomic network kinase-dependent processing events remains poorly defined. Here, we explore connectivity functions by applying graduated, short-exposure, pharmacological inhibition using a novel small molecule (T3) with very high potency, selectivity, and cell-based stability. Using RNA-Seq, define kinase-responsive alternative events, large majority which monotonically...
With the aim of discovering a selective kinase inhibitor targeting pan-RAF inhibition, we designed novel 1,3-benzothiazole derivatives based on our thiazolo[5,4-b]pyridine class RAF/VEGFR2 1 and developed regioselective cyclization methodology for C-7-substituted scaffold utilizing meta-substituted anilines. Eventually, selected 7-cyano derivative 8B (TAK-632) as development candidate confirmed its binding mode by cocrystal structure with BRAF. Accommodation group into BRAF-selectivity...
Glycogen synthase kinase 3beta (GSK-3beta) inhibition is expected to be a promising therapeutic approach for treating Alzheimer's disease. Previously we reported series of 1,3,4-oxadiazole derivatives as potent and highly selective GSK-3beta inhibitors, however, the representative compounds 1a,b showed poor pharmacokinetic profiles. Efforts were made address this issue by reducing molecular weight lipophilicity, leading identification oxadiazole containing sulfinyl group, (S)-9b (S)-9c....
Alzheimer's disease (AD) is a neurodegenerative disorder leading to progressive loss of cognitive function and pathologically characterized by senile plaques neurofibrillary tangles. Glycogen synthase kinase-3 (GSK-3) involved in AD pathogenesis. GSK-3 reported not only phosphorylate tau, major component tangles, but also regulate the production amyloid β, which deposited plaques. Therefore, pharmacological inhibition considered an attractive therapeutic approach. In this study, we report...
A next generation cancer drug candidate, a CDC7 inhibitor, TAK-931, was developed, which is being evaluated in clinical trials.
Myeloid progenitor cells give rise to a variety of progenies including dendritic cells. However, the mechanism controlling diversification myeloid progenitors into each progeny is largely unknown. PU.1 and CCAAT/enhancing binding protein (C/EBP) family transcription factors have been characterized as key regulators for development function system. roles C/EBP not fully identified because functional redundancy among members. Using high titer–retroviral infection, we demonstrate that...
Polo-like kinase 1 (PLK1) is a serine/threonine protein involved in key processes during mitosis. Human PLK1 has been shown to be overexpressed various human cancers, and elevated levels of have associated with poor prognosis, making it an attractive target for anticancer therapy. TAK-960 [4-[(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino]-2-fluoro-5-methoxy-N-(1-methylpiperidin-4-yl) benzamide] novel, investigational, orally...
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...
Phosphodiesterase (PDE) 2A inhibitors have emerged as a novel mechanism with potential therapeutic option to ameliorate cognitive dysfunction in schizophrenia or Alzheimer's disease through upregulation of cyclic nucleotides the brain and thereby achieve potentiation nucleotide signaling pathways. This article details expedited optimization our recently disclosed pyrazolo[1,5-a]pyrimidine lead compound 4b, leading discovery clinical candidate 36 (TAK-915), which demonstrates an appropriate...
Deoxyhypusine synthase (DHPS) utilizes spermidine and NAD as cofactors to incorporate a hypusine modification into the eukaryotic translation initiation factor 5A (eIF5A). Hypusine is essential for eIF5A activation, which, in turn, plays key role regulating protein of selected mRNA that are associated with synthesis oncoproteins, thereby enhancing tumor cell proliferation. Therefore, inhibition DHPS promising therapeutic option treatment cancer. To discover novel lead compounds target DHPS,...
Cathepsin S inhibitors are well-known to be an attractive target as immunological therapeutic agents. Recently, our gene expression analysis identified that cathepsin could also effective for neuropathic pain. Herein, we describe the efficacy of selective antihyperalgesics in a model pain rats after oral administration.
Retinoic acid receptor-related orphan receptor γt (RORγt) agonists are expected to provide a novel class of immune-activating anticancer drugs via activation Th17 cells and Tc17 cells. Herein, we describe structure-based functionality switching approach from in house well-optimized RORγt inverse potent agonists. We succeeded the identification agonist 5 without major chemical structure change. The biochemical response was validated by molecular dynamics simulation studies that showed helix...
In our pursuit of developing a novel, potent, and selective cell division cycle 7 (Cdc7) inhibitor, we optimized the previously reported thieno[3,2-d]pyrimidinone analogue I showing time-dependent Cdc7 kinase inhibition slow dissociation kinetics. These medicinal chemistry efforts led to identification compound 3d, which exhibited potent cellular activity, excellent selectivity, antitumor efficacy in COLO205 xenograft mouse model. However, issue formaldehyde adduct formation emerged during...
On the basis of pyrrolopyrimidine core structure that was previously discovered, cathepsin K inhibitors having a spiro amine at P3 have been explored to enhance target, bone marrow, tissue distribution. Several structures were identified with improved distribution toward marrow. The representative inhibitor 7 this series revealed in vivo reduction C-terminal telopeptide type I collagen rats and monkeys.
It has been hypothesized that selective inhibition of phosphodiesterase (PDE) 2A could potentially be a novel approach to treat cognitive impairment in neuropsychiatric and neurodegenerative disorders through augmentation cyclic nucleotide signaling pathways brain regions associated with learning memory. Following our earlier work, this article describes drug design strategy for new series lead compounds structurally distinct from clinical candidate 2 (TAK-915), subsequent medicinal...
Deoxyhypusine synthase (DHPS) is the primary enzyme responsible for hypusine modification and, thereby, activation of eukaryotic translation initiation factor 5A (eIF5A), which key in regulating protein processes associated with tumor proliferation. Although DHPS inhibitors could be a promising therapeutic option treating cancer, only few studies reported druglike compounds this inhibition property. Thus, work, we designed and synthesized new chemical series possessing fused ring scaffolds...
O-GlcNAcase (OGA) has received increasing attention as an attractive therapeutic target for tau-mediated neurodegenerative disorders; however, its role in these pathologies remains unclear. Therefore, potent chemical tools with favorable pharmacokinetic profiles are desirable to characterize this enzyme. Herein, we report the discovery of a and novel OGA inhibitor, compound 5i, comprising aminopyrimidine scaffold, identified by virtual screening based on multiple methodologies combining...
A case of a 39 year-old Japanese woman with dome-shaped elevated nodule on the frontal region scalp is reported. Our very similar both clinically and histologically to that ‘giant solitary sebaceous gland hyperplasia’ described by Kudoh et al. in 1988.