scispace - formally typeset
Search or ask a question
Author

Takashi Ono

Bio: Takashi Ono is an academic researcher from Mitsubishi Tanabe Pharma. The author has contributed to research in topics: Rho kinase inhibitor & Triple helix. The author has an hindex of 5, co-authored 12 publications receiving 3088 citations.

Papers
More filters
Journal ArticleDOI
30 Oct 1997-Nature
TL;DR: Pyridine derivative Y-27632 consistently suppresses Rho-induced, p160ROCK-mediated formation of stress fibres in cultured cells and dramatically corrects hypertension in several hypertensive rat models, suggesting that compounds that inhibit this process might be useful therapeutically.
Abstract: Abnormal smooth-muscle contractility may be a major cause of disease states such as hypertension, and a smooth-muscle relaxant that modulates this process would be useful therapeutically. Smooth-muscle contraction is regulated by the cytosolic Ca2+ concentration and by the Ca2+ sensitivity of myofilaments: the former activates myosin light-chain kinase and the latter is achieved partly by inhibition of myosin phosphatase. The small GTPase Rho and its target, Rho-associated kinase, participate in this latter mechanism in vitro, but their participation has not been demonstrated in intact muscles. Here we show that a pyridine derivative, Y-27632, selectively inhibits smooth-muscle contraction by inhibiting Ca2+ sensitization. We identified the Y-27632 target as a Rho-associated protein kinase, p160ROCK. Y-27632 consistently suppresses Rho-induced, p160ROCK-mediated formation of stress fibres in cultured cells and dramatically corrects hypertension in several hypertensive rat models. Our findings indicate that p160ROCK-mediated Ca2+ sensitization is involved in the pathophysiology of hypertension and suggest that compounds that inhibit this process might be useful therapeutically.

2,900 citations

Patent
08 Aug 1997
TL;DR: Novel medicines comprising Rho kinase inhibitors, such as hypertension remedy, angina remedy, cerebrovascular twitching inhibitor, asthma remedy, premature birth preventive, arteriosclerosis remedy, anticancer drug, anti-phlogistic, immunosuppressive, autoimmune disease remedy, anti AIDS drug, contraceptive, digestive infection preventive, osteoporosis remedy, retinopathy remedy, and cerebral function ameliorant.
Abstract: Novel medicines comprising Rho kinase inhibitors, such as hypertension remedy, angina remedy, cerebrovascular twitching inhibitor, asthma remedy, premature birth preventive, arteriosclerosis remedy, anticancer drug, anti-phlogistic, immunosuppressive, autoimmune disease remedy, anti-AIDS drug, contraceptive, digestive infection preventive, osteoporosis remedy, retinopathy remedy, and cerebral function ameliorant; and reagents and diagnostic agents comprising Rho kinase inhibitors.

160 citations

Patent
08 Aug 1997
TL;DR: In this paper, a Rho kinase inhibitor is provided as a novel pharmaceutical agent, particularly as a therapeutic agent of hypertension, a therapeutic agents of angina pectoris, a suppressive agent of cerebrovascular contraction.
Abstract: A Rho kinase inhibitor is provided as a novel pharmaceutical agent, particularly as a therapeutic agent of hypertension, a therapeutic agent of angina pectoris, a suppressive agent of cerebrovascular contraction, a therapeutic agent of asthma, a therapeutic agent of peripheral circulation disorder, a prophylactic agent of immature birth, a therapeutic agent of arteriosclerosis, an anti-cancer drug, an anti-inflammatory agent, an immunosuppressant, a therapeutic agent of autoimmune disease, an anti-AIDS drug, a contraceptive, a prophylactic agent of digestive tract infection, a therapeutic agent of osteoporosis, a therapeutic agent of retinopathy and a brain function improving drug. In addition, the Rho kinase inhibitor is provided as a reagent and a diagnostic.

58 citations

Journal ArticleDOI
TL;DR: Novel methods are established by adopting a time-resolved FRET technique in vitro and a bimolecular fluorescence complementation technique in vivo to provide direct evidence that Hsp47 binds to collagen triple helices but not to the monomer form in vitro.

41 citations

Journal ArticleDOI
TL;DR: It is suggested that in cells treated with DMDC at a high concentration, an effective DMDCTP level is maintained for an extended period after washing out the compound from the medium, and cells in S phase are rapidly killed by the treatment but are temporarily prevented or delayed entry into the drug-sensitive S phase.

14 citations


Cited by
More filters
Journal ArticleDOI
12 Dec 2002-Nature
TL;DR: Rho GTPases are molecular switches that control a wide variety of signal transduction pathways in all eukaryotic cells and their ability to influence cell polarity, microtubule dynamics, membrane transport pathways and transcription factor activity is probably just as significant.
Abstract: Rho GTPases are molecular switches that control a wide variety of signal transduction pathways in all eukaryotic cells. They are known principally for their pivotal role in regulating the actin cytoskeleton, but their ability to influence cell polarity, microtubule dynamics, membrane transport pathways and transcription factor activity is probably just as significant. Underlying this biological complexity is a simple biochemical idea, namely that by switching on a single GTPase, several distinct signalling pathways can be coordinately activated. With spatial and temporal activation of multiple switches factored in, it is not surprising to find Rho GTPases having such a prominent role in eukaryotic cell biology.

4,616 citations

Journal ArticleDOI
TL;DR: The results demonstrate that the specificities of protein kinase inhibitors cannot be assessed simply by studying their effect on kinases that are closely related in primary structure, and proposes guidelines for the use of protein Kinase inhibitors in cell-based assays.
Abstract: The specificities of 28 commercially available compounds reported to be relatively selective inhibitors of particular serine/threonine-specific protein kinases have been examined against a large panel of protein kinases. The compounds KT 5720, Rottlerin and quercetin were found to inhibit many protein kinases, sometimes much more potently than their presumed targets, and conclusions drawn from their use in cell-based experiments are likely to be erroneous. Ro 318220 and related bisindoylmaleimides, as well as H89, HA1077 and Y 27632, were more selective inhibitors, but still inhibited two or more protein kinases with similar potency. LY 294002 was found to inhibit casein kinase-2 with similar potency to phosphoinositide (phosphatidylinositol) 3-kinase. The compounds with the most impressive selectivity profiles were KN62, PD 98059, U0126, PD 184352, rapamycin, wortmannin, SB 203580 and SB 202190. U0126 and PD 184352, like PD 98059, were found to block the mitogen-activated protein kinase (MAPK) cascade in cell-based assays by preventing the activation of MAPK kinase (MKK1), and not by inhibiting MKK1 activity directly. Apart from rapamycin and PD 184352, even the most selective inhibitors affected at least one additional protein kinase. Our results demonstrate that the specificities of protein kinase inhibitors cannot be assessed simply by studying their effect on kinases that are closely related in primary structure. We propose guidelines for the use of protein kinase inhibitors in cell-based assays.

4,091 citations

Journal ArticleDOI
TL;DR: Harmine has been identified as a potent and specific inhibitor of DYRK1A (dual-specificity tyrosine-phosphorylated and -regulated kinase 1A) in vitro and the results have further emphasized the need for considerable caution in using small-molecule inhibitors of protein kinases to assess the physiological roles of these enzymes.
Abstract: The specificities of 65 compounds reported to be relatively specific inhibitors of protein kinases have been profiled against a panel of 70-80 protein kinases. On the basis of this information, the effects of compounds that we have studied in cells and other data in the literature, we recommend the use of the following small-molecule inhibitors: SB 203580/SB202190 and BIRB 0796 to be used in parallel to assess the physiological roles of p38 MAPK (mitogen-activated protein kinase) isoforms, PI-103 and wortmannin to be used in parallel to inhibit phosphatidylinositol (phosphoinositide) 3-kinases, PP1 or PP2 to be used in parallel with Src-I1 (Src inhibitor-1) to inhibit Src family members; PD 184352 or PD 0325901 to inhibit MKK1 (MAPK kinase-1) or MKK1 plus MKK5, Akt-I-1/2 to inhibit the activation of PKB (protein kinase B/Akt), rapamycin to inhibit TORC1 [mTOR (mammalian target of rapamycin)-raptor (regulatory associated protein of mTOR) complex], CT 99021 to inhibit GSK3 (glycogen synthase kinase 3), BI-D1870 and SL0101 or FMK (fluoromethylketone) to be used in parallel to inhibit RSK (ribosomal S6 kinase), D4476 to inhibit CK1 (casein kinase 1), VX680 to inhibit Aurora kinases, and roscovitine as a pan-CDK (cyclin-dependent kinase) inhibitor. We have also identified harmine as a potent and specific inhibitor of DYRK1A (dual-specificity tyrosine-phosphorylated and -regulated kinase 1A) in vitro. The results have further emphasized the need for considerable caution in using small-molecule inhibitors of protein kinases to assess the physiological roles of these enzymes. Despite being used widely, many of the compounds that we analysed were too non-specific for useful conclusions to be made, other than to exclude the involvement of particular protein kinases in cellular processes.

2,527 citations

Journal ArticleDOI
TL;DR: A personal view of some of the most important advances that have shaped this field of protein kinases, after G-protein-coupled receptors.
Abstract: Protein phosphorylation regulates most aspects of cell life, whereas abnormal phosphorylation is a cause or consequence of disease. A growing interest in developing orally active protein-kinase inhibitors has recently culminated in the approval of the first of these drugs for clinical use. Protein kinases have now become the second most important group of drug targets, after G-protein-coupled receptors. Here, I give a personal view of some of the most important advances that have shaped this field.

2,113 citations

Journal ArticleDOI
TL;DR: The main focus of this review will be Rho, Rac and Cdc42, the three best characterized mammalian Rho GTPases, though the genetic analysis of RhoGTPases in lower eukaryotes is making increasingly important contributions to this field.
Abstract: Rho GTPases are molecular switches that regulate many essential cellular processes, including actin dynamics, gene transcription, cell-cycle progression and cell adhesion. About 30 potential effector proteins have been identified that interact with members of the Rho family, but it is still unclear which of these are responsible for the diverse biological effects of Rho GTPases. This review will discuss how Rho GTPases physically interact with, and regulate the activity of, multiple effector proteins and how specific effector proteins contribute to cellular responses. To date most progress has been made in the cytoskeleton field, and several biochemical links have now been established between GTPases and the assembly of filamentous actin. The main focus of this review will be Rho, Rac and Cdc42, the three best characterized mammalian Rho GTPases, though the genetic analysis of Rho GTPases in lower eukaryotes is making increasingly important contributions to this field.

2,056 citations