Discovery of a novel IKK-β inhibitor by ligand-based virtual screening techniques

There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

Graphical abstract

Abstract

Various inflammatory stimuli that activate the nuclear factor kappa B (NF-κB) signaling pathway converge on a serine/threonine kinase that displays a key role in the activation of NF-κB: the I kappa B kinase β (IKK-β). Therefore, IKK-β is considered an interesting target for combating inflammation and cancer. In our study, we developed a ligand-based pharmacophore model for IKK-β inhibitors. This model was employed to virtually screen commercial databases, giving a focused hit list of candidates. Subsequently, we scored by molecular shape to rank and further prioritized virtual hits by three-dimensional shape-based alignment. One out of ten acquired and biologically tested compounds showed inhibitory activity in the low micromolar range on IKK-β enzymatic activity in vitro and on NF-κB transactivation in intact cells. Compound 8 (2-(1-adamantyl)ethyl 4-[(2,5-dihydroxyphenyl)methylamino]benzoate) represents a novel chemical class of IKK-β inhibitors and shows that the presented model is a valid approach for identification and development of new IKK-β ligands.

Related collections

Most cited references 35

Record: found
Abstract: found
Article: not found

Attenuation of murine collagen-induced arthritis by a novel, potent, selective small molecule inhibitor of IkappaB Kinase 2, TPCA-1 (2-[(aminocarbonyl)amino]-5-(4-fluorophenyl)-3-thiophenecarboxamide), occurs via reduction of proinflammatory cytokines and antigen-induced T cell Proliferation.

Leigh F Callahan, Amy K Roshak, Christopher Evans … (2004)

Demonstration that IkappaB kinase 2 (IKK-2) plays a pivotal role in the nuclear factor-kappaB-regulated production of proinflammatory molecules by stimuli such as tumor necrosis factor (TNF)-alpha and interleukin (IL)-1 suggests that inhibition of IKK-2 may be beneficial in the treatment of rheumatoid arthritis. In the present study, we demonstrate that a novel, potent (IC(50) = 17.9 nM), and selective inhibitor of human IKK-2, 2-[(aminocarbonyl)amino]-5-(4-fluorophenyl)-3-thiophenecarboxamide (TPCA-1), inhibits lipopolysaccharide-induced human monocyte production of TNF-alpha, IL-6, and IL-8 with an IC(50) = 170 to 320 nM. Prophylactic administration of TPCA-1 at 3, 10, or 20 mg/kg, i.p., b.i.d., resulted in a dose-dependent reduction in the severity of murine collagen-induced arthritis (CIA). The significantly reduced disease severity and delay of disease onset resulting from administration of TPCA-1 at 10 mg/kg, i.p., b.i.d. were comparable to the effects of the antirheumatic drug, etanercept, when administered prophylactically at 4 mg/kg, i.p., every other day. Nuclear localization of p65, as well as levels of IL-1beta, IL-6, TNF-alpha, and interferon-gamma, were significantly reduced in the paw tissue of TPCA-1- and etanercept-treated mice. In addition, administration of TPCA-1 in vivo resulted in significantly decreased collagen-induced T cell proliferation ex vivo. Therapeutic administration of TPCA-1 at 20 mg/kg, but not at 3 or 10 mg/kg, i.p., b.i.d., significantly reduced the severity of CIA, as did etanercept administration at 12.5 mg/kg, i.p., every other day. These results suggest that reduction of proinflammatory mediators and inhibition of antigen-induced T cell proliferation are mechanisms underlying the attenuation of CIA by the IKK-2 inhibitor, TPCA-1.

0 comments Cited 97 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: not found

A selective novel low-molecular-weight inhibitor of IkappaB kinase-beta (IKK-beta) prevents pulmonary inflammation and shows broad anti-inflammatory activity.

Katsuya Sakai, Florian Gantner, Hiroshi Komura … (2005)

1 Pulmonary inflammatory diseases such as asthma are characterized by chronic, cell-mediated inflammation of the bronchial mucosa. 2 Recruitment and activation of inflammatory cells is orchestrated by a variety of mediators such as cytokines, chemokines, or adhesion molecules, the expression of which is regulated via the transcription factor nuclear factor kappa B (NF-kappaB). 3 NF-kappaB signaling is controlled by the inhibitor of kappa B kinase complex (IKK), a critical catalytic subunit of which is IKK-beta. 4 We identified COMPOUND A as a small-molecule, ATP-competitive inhibitor selectively targeting IKK-beta kinase activity with a K(i) value of 2 nM. 5 COMPOUND A inhibited stress-induced NF-kappaB transactivation, chemokine-, cytokine-, and adhesion molecule expression, and T- and B-cell proliferation. 6 COMPOUND A is orally bioavailable and inhibited the release of LPS-induced TNF-alpha in rodents. 7 In mice COMPOUND A inhibited cockroach allergen-induced airway inflammation and hyperreactivity and efficiently abrogated leukocyte trafficking induced by carrageenan in mice or by ovalbumin in a rat model of airway inflammation. 8 COMPOUND A was well tolerated by rodents over 3 weeks without affecting weight gain. 9 Furthermore, in mice COMPOUND A suppressed edema formation in response to arachidonic acid, phorbol ester, or edema induced by delayed-type hypersensitivity. 10 These data suggest that IKK-beta inhibitors offer an effective therapeutic approach for inhibiting chronic pulmonary inflammation.

0 comments Cited 48 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: not found

Design and preparation of 2-benzamido-pyrimidines as inhibitors of IKK.

Rudolf Waelchli, Birgit Bollbuck, Christian Bruns … (2006)

The design, synthesis, and the biological evaluation of 2-benzamido-pyrimidines as novel IKK inhibitors are described. By optimization of the lead compound 3, compounds 16 and 24 are identified as good inhibitors of IKK2 with IC(50) values of 40 and 25 nM, respectively. Compound 16 also demonstrated significant in vivo activity in an acute model of cytokine release.

0 comments Cited 47 times – based on 0 reviews      Review now

Bookmark

All references

Author and article information

Journal

Journal ID (nlm-ta): Bioorg Med Chem Lett

Journal ID (iso-abbrev): Bioorg. Med. Chem. Lett

Title: Bioorganic & Medicinal Chemistry Letters

Publisher: Elsevier Science Ltd

ISSN (Print): 0960-894X

ISSN (Electronic): 1464-3405

Publication date PMC-release: 01 January 2011

Publication date (Print): 01 January 2011

Volume: 21

Issue: 1

Pages: 577-583

Affiliations

[a ]Institute of Pharmacy, Department of Pharmaceutical Chemistry, Computer-Aided Molecular Design Group and Center of Molecular Biosciences Innsbruck—CMBI, University of Innsbruck, Innrain 52c, A-6020 Innsbruck, Austria

[b ]Institute of Pharmacy, Department of Pharmacognosy and Center for Molecular Biosciences Innsbruck, University of Innsbruck, Innrain 52c, A-6020 Innsbruck, Austria

[c ]Department of Pharmacognosy, University of Vienna, Althanstr. 14, A-1090 Vienna, Austria

[d ]Institute of Pharmacy, Computer-Aided Drug Design, Freie Universität Berlin, Königin-Luisestrasse 2+4, D-14194 Berlin, Germany

[e ]Inte:Ligand Softwareentwicklung und Consulting GmbH, Mariahilferstr. 74b/11, A-1070 Vienna, Austria

Author notes

[* ]Corresponding author. Tel.: +49 30 83852686. gerhard.wolber@ 123456uibk.ac.at wolber@ 123456zedat.fu-berlin.de

[†]

Present address: Faculty of Pharmacy, Gadjah Mada University, Sekip Utara, Yogyakarta 55281, Indonesia.

Article

Publisher ID: BMCL16625

DOI: 10.1016/j.bmcl.2010.10.051

PMC ID: 3013379

PubMed ID: 21078555

SO-VID: fe789539-d65d-486b-a758-708ce9ccdcad

License:

This document may be redistributed and reused, subject to certain conditions.

History

Date received : 30 August 2010

Date revision received : 8 October 2010

Date accepted : 9 October 2010

Comments

Comment on this article

scite_

Smart Citations

Citing PublicationsSupportingMentioningContrasting

View Citations

See how this article has been cited at scite.ai

scite shows how a scientific paper has been cited by providing the context of the citation, a classification describing whether it supports, mentions, or contrasts the cited claim, and a label indicating in which section the citation was made.