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Nakagomi M.,Research Foundation Itsuu Laboratory | Fujimaki N.,Research Foundation Itsuu Laboratory | Ito A.,Research Foundation Itsuu Laboratory | Toda T.,Research Foundation Itsuu Laboratory | And 3 more authors.
PLoS ONE | Year: 2013

Firefly luciferase (Luc) is widely used as a reporter enzyme in cell-based assays for gene expression. A novel aromatic carboxylic acid, F-53, reported here for the first time, substantially inhibited the enzymatic activity of Luc in a Luc reporter screening. Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS) and tandem mass spectrometry (MS/MS) analyses showed that F-53 modifies Luc at lysine-529 via amidation of the F-53 carboxyl group. The lysine-529 residue of Luc, which plays a regulatory catalytic role, can be acetylated. Luc also has a long-chain fatty acyl-CoA synthase activity. An in vitro assay that involved both recombinant Luc and mouse liver microsomes identified F-53-CoA as the reactive form produced from F-53. However, whereas the inhibitory effect of F-53 is observed in Hela cells that transiently expressed Luc, it is not observed in an in vitro assay that involves recombinant Luc alone. Therefore, insights into the activities of certain mammalian transferases can be translated to better understand the acylation by F-53. The insights from this study about the novel inhibitory modification mechanism might help not only to avoid misinterpretation of the results of Luc-based reporter screening assays but also to explain the pharmacological and toxicological effects of carboxylic acid-containing drugs. © 2013 Nakagomi et al.

Ohta K.,Tohoku Pharmaceutical University | Kawachi E.,Tokyo Medical and Dental University | Fukasawa H.,Institute of Medicinal Molecular Design Inc. | Shudo K.,Research Foundation Itsuu Laboratory | Kagechika H.,Tokyo Medical and Dental University
Bioorganic and Medicinal Chemistry | Year: 2011

Based upon the structure-activity relationships of diphenylamine derivatives with retinoid synergistic activity (RXR agonists), novel diphenylamine derivatives with a long alkyl chain (9a and 9b) or a benzyl group (10a-f) as the N-substituent were designed and synthesized. All the synthesized compounds dose-dependently inhibited HL-60 cell differentiation induced by 3.3 × 10 -10 M Am80. Among them, compound 10f showed the most potent inhibitory activity, and the mechanism was shown, by means of transactivation assay for RARs and RXRs, to involve antagonism against RARs. The N-substituent of the diphenylamine skeleton plays an important role in determining the receptor selectivity for RARs or RXRs, as well as the agonist or antagonist nature of the activity. © 2011 Elsevier Ltd. All rights reserved.

Institute of Medicinal Molecular Design Inc. | Date: 2011-04-15

A method of generating a molecule-function network including bio-events by carrying out a connect search using a biomolecule-linkage database including information on the bio-events, and a method of predicting a pathway between an arbitrary biomolecule and an arbitrary bio-event in said network or a method of predicting the bio-events to which an arbitrary biomolecule in said network is related.

Shionogi & Co. and Institute Of Medicinal Molecular Design Inc. | Date: 2011-06-30

Disclosed is a compound which is useful as an 11-hydroxysteroid dehydrogenase type 1 inhibitor. A compound represented by the formula: its pharmaceutically acceptable salt, or a solvate thereof,

Suzuki J.-I.,Bunkyo University | Ogawa M.,Bunkyo University | Muto S.,Institute of Medicinal Molecular Design Inc. | Itai A.,Institute of Medicinal Molecular Design Inc. | And 3 more authors.
Expert Opinion on Investigational Drugs | Year: 2011

NF-κB is a key regulator of inflammation and immunity in cancer development. The IκB kinase (IKK) is a multisubunit complex containing catalytic subunits termed IKK-α, -β and -γ. It is well known that many pro-inflammatory stimuli require the IKK-β subunit for NF-κB activation. Areas covered: NF-κB affects the progression of inflammation-related diseases, such as myocardial ischemia, bronchial asthma, arthritis, cancer and other diseases. We review the characteristics and effects of these inhibitors on inflammatory and other diseases. Expert opinion: Various synthesized IKK inhibitors have been developed and they will be used clinically in the near future. © 2011 Informa UK, Ltd.

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