A5103276998- Microtubule and mitosis dynamics
- Cancer-related Molecular Pathways
- Cancer, Hypoxia, and Metabolism
- Acute Myeloid Leukemia Research
- Lymphoma Diagnosis and Treatment
- Bone Metabolism and Diseases
- Cancer Treatment and Pharmacology
- Chronic Lymphocytic Leukemia Research
- RNA modifications and cancer
- Advanced biosensing and bioanalysis techniques
- RNA Research and Splicing
- RNA and protein synthesis mechanisms
- Lung Cancer Research Studies
- Histone Deacetylase Inhibitors Research
- Protease and Inhibitor Mechanisms
- Epigenetics and DNA Methylation
- Liver Disease and Transplantation
- Organ Transplantation Techniques and Outcomes
- 14-3-3 protein interactions
- Chemical Synthesis and Analysis
- Chromatin Remodeling and Cancer
- Neuroendocrine Tumor Research Advances
- Cancer Mechanisms and Therapy
- Blood disorders and treatments
- Estrogen and related hormone effects
Takeda (Japan)
1999-2020
Takeda (United States)
2013
Hokushin General Hospital
2004
Osaka Medical and Pharmaceutical University
1991-2002
Fujita Health University
1992-1997
Kanazawa University
1992
Toho University
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...
Accumulating evidence has demonstrated the importance of alternative splicing in various physiological processes, including development different diseases. CDC-like kinases (CLKs) and serine-arginine protein (SRPKs) are components machinery that crucial for exon selection. The discovery small molecule inhibitors against these is significant value, not only to delineate molecular mechanisms splicing, but also identify potential therapeutic opportunities. Here we describe a series molecules...
Dysregulation of lysine (K)-specific demethylase 1A (LSD1), also known as KDM1A, has been implicated in the development various cancers, including leukemia. Here, we describe antileukemic activity and mechanism action T-3775440, a novel irreversible LSD1 inhibitor. Cell growth analysis leukemia cell lines revealed that acute erythroid (AEL) megakaryoblastic cells (AMKL) were highly sensitive to this compound. T-3775440 treatment enforced transdifferentiation erythroid/megakaryocytic lineages...
T-3775440 is an irreversible inhibitor of the chromatin demethylase LSD1, which exerts antiproliferative effects by disrupting interaction between LSD1 and GFI1B, a SNAG domain transcription factor, inducing leukemia cell transdifferentiation. Here, we describe anticancer mechanism action in small-cell lung cancer (SCLC). inhibited proliferation SCLC cells vitro retarded tumor growth vivo disrupted transcriptional repressor INSM1, thereby inhibiting expression neuroendocrine-associated...
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...
Balloon-occluded retrograde transvenous obliteration is an effective new method for treating gastric fundal varices, but subsequent occurrence of esophageal varices creates a problem. The relationship between portal hemodynamics and the after prophylactic balloon-occluded was investigated.Ten cirrhotic patients considered to have high risk underwent angiography. Six showed communication blood flow in wall vessels that gastrorenal shunt (type I), whereas others II) did not. Depending on...
We have determined the three dimensional structure of complex human cathepsin L and E-64, an irreversible inhibitor cysteine proteases, at 2.5 A resolution. The overall was similar to that other known proteases apparently identical mature region procathepsin L. electron density for E-64 is clearly visible except guanidinobutane moiety. From comparison active sites B, we found following: (1) S' subsites B are totally different because 'occluding loop' lying on end B. (2) S2 pocket shallow...
Cathepsin L, a lysosomal cysteine protease, is secreted by osteoclasts and participates in bone collagen degradation. In search for cathepsin L inhibitors as antiosteoporotic agents, series of peptide aldehyde derivatives were prepared two synthetic approaches, DMSO oxidation the corresponding alcohol DIBAL-H reduction N, O-dimethylhydroxylamide derivatives, evaluated inhibitory activity against human effects on resorption. Some including alpha-acylamino showed potent activities. Among these...
Abstract Protein kinases Aurora A, B, and C play essential roles during mitosis cell division, are frequently elevated in cancer, represent attractive targets for therapeutic intervention. TAK-901 is an investigational, multitargeted B kinase inhibitor derived from a novel azacarboline hinge-binder chemotype. exhibited time-dependent, tight-binding inhibition of but not A. Consistent with inhibition, suppressed cellular histone H3 phosphorylation induced polyploidy. In various human cancer...
Abstract Lysine-specific demethylase 1A (LSD1, KDM1A) specifically demethylates di- and monomethylated histones H3K4 K9, resulting in context-dependent transcriptional repression or activation. We previously identified an irreversible LSD1 inhibitor T-3775440, which exerts antileukemic activities a subset of acute myeloid leukemia (AML) cell lines by inducing transdifferentiation. The NEDD8-activating enzyme pevonedistat (MLN4924, TAK-924) is investigational drug with antiproliferative AML,...
<i>Background:</i> Elderly people frequently have symptoms of fullness and appetite loss due to impaired gastric motor activity. These may cause malnutrition, immunosuppression other complications. <i>Objective:</i> The effects aging daily activity on motility in the elderly were investigated by electrogastrography <sup>13</sup>C-acetate breath test. <i>Methods:</i> We enrolled seven active subjects (active group), staying at a geriatric...
Background: As the global population ages, there is an increasing demand for effective strategies to maintain and improve health among older adults. Wearable technology presents a promising tool monitoring management, yet its effectiveness in comprehensive improvement adults remains uncertain. Objective: This study aimed evaluate of personalized lifestyle notifications, based on wearable device recorded data, improving outcomes, specifically cognitive physical function, adults, compared...
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...
Emerging evidence indicates that alternative splicing plays a critical role in cancer progression through abnormal expression or mutation of factors. Small-molecule modulators have recently attracted considerable attention as novel class therapeutics. CDC-like kinases (CLKs) are central to exon recognition mRNA and CLK inhibitors exhibit anti-tumour activities. Most importantly, molecular mechanism-based combination strategies for therapy must be considered. However, it remains unclear...
Thirty-two patients with advanced non-Hodgkin's lymphoma (NHL) aggressive histologic findings were treated cyclophosphamide, doxorubicin, methotrexate leucovorin rescue, bleomycin, vincristine, etoposide, ifosfamide, and prednisolone (CAMBO-VIP), in which presumably non-cross-resistant myelosuppressive nonmyelosuppressive agents administered during alternate weeks for 12 weeks. To ensure the high-dose intensity of protocol, dose reduction delay treatment minimized. Three inadequately....
Several reports have shown that the overexpression of MET proto-oncogene, receptor tyrosine kinase (MET), was more frequently observed in clear cell carcinoma (CCC) than non-CCC. We evaluated antitumor activity cabozantinib, targets MET.A gene expression analysis tumors from human ovarian cancers carried out by transcriptome sequencing. An vitro 3-(4, 5-dimethylthiazolyl-2)-2, 5-diphenyltetrazolium bromide assay (MTT assay) and vivo experiments were performed to determine cabozantinib.The...
<div>Abstract<p>T-3775440 is an irreversible inhibitor of the chromatin demethylase LSD1, which exerts antiproliferative effects by disrupting interaction between LSD1 and GFI1B, a SNAG domain transcription factor, inducing leukemia cell transdifferentiation. Here, we describe anticancer mechanism action T-3775440 in small-cell lung cancer (SCLC). inhibited proliferation SCLC cells <i>in vitro</i> retarded tumor growth vivo</i>. disrupted transcriptional...