Attenuation of collagen-induced arthritis by orally available imidazoline-based NF-κB inhibitors

Lansdell, Theresa A.; O’Reilly, Sandra; Woolliscroft, Tracey; Azevedo, Lauren M.; Kahlon, Daljinder K.; Hovde, Stacy; McCormick, J. Justin; Henry, R. William; Cornicelli, Joseph A.; Tepe, Jetze J.

doi:10.1016/j.bmcl.2012.05.056

Cited by 6 publications

(12 citation statements)

References 19 publications

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“…11 Although these non-competitive inhibitors exhibit good in vivo efficacy, the discovery of agents with increased potency would be a significant step toward the potential clinical development of this new type of proteasome modulation. Herein, we report the optimization of the imidazoline scaffold as non-competitive proteasome inhibitors with IC 50 values in the nanomolar range.…”

Section: Introductionmentioning

confidence: 99%

“…8,9 We previously reported the activity of the noncompetitive proteasome inhibitor, TCH-013, in purified protein systems, cell culture, and in vivo models of multiple myeloma 10 and arthritis. 11 Although these noncompetitive inhibitors exhibit good in vivo efficacy, the discovery of agents with increased potency would be a significant step toward the potential clinical development of this new type of proteasome modulation. Herein, we report the optimization of the imidazoline scaffold as noncompetitive proteasome inhibitors with IC 50 values in the nanomolar range.…”

Section: ■ Introductionmentioning

confidence: 99%

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Inhibition of the Human Proteasome by Imidazoline Scaffolds

et al. 2013

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The proteasome has emerged as the primary target for the treatment of multiple myeloma. Unfortunately, nearly all patients develop resistance to competitive-type proteasome inhibitors, such as bortezomib. Herein, we describe the optimization of non-competitive proteasome inhibitors to yield derivatives that exhibit nanomolar potency (compound 46, IC50 130 nM) towards proteasome inhibition and overcome bortezomib resistance. These studies illustrate the feasibility of the development of non-competitive proteasome inhibitors as additives and/or alternatives to competitive proteasome inhibitors.

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Section: Introductionmentioning

confidence: 99%

Section: ■ Introductionmentioning

confidence: 99%

Inhibition of the Human Proteasome by Imidazoline Scaffolds

et al. 2013

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“…This dosing regimen did not indicate any detectable anemia, gross neurologic toxicity (data not shown), weight loss, or liver toxicity as earlier reported. 40 In a log-linear regression model of the mice during treatment (SFig. 10), the mean tumor volume doubling time was 6.3 days for the vehicle treated group and >25 days for TCH-013 (P < 0.0001).…”

Section: Resultsmentioning

confidence: 98%

“…Resistance to bortezomib has been demonstrated to occur through several different mechanisms, including the overexpression of mutated catalytic subunits of the proteasome, 24, 25 which is the site in the proteasome where bortezomib and all other proteasome inhibitors under clinical evaluation bind 11 . In this study, we examined TCH-013, a non-peptide based, small molecule NF-κB inhibitor 40, 41 . Michaelis-Menton kinetics demonstrates that TCH-013 inhibits the CT-L and Casp-L activities of the 20S proteasome via non-competitively kinetics.…”

Section: Resultsmentioning

confidence: 99%

Noncompetitive Modulation of the Proteasome by Imidazoline Scaffolds Overcomes Bortezomib Resistance and Delays MM Tumor Growth in Vivo

Lansdell¹,

Hurchla

Xiang

et al. 2012

ACS Chem. Biol.

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Multiple myeloma is a malignant disorder of differentiated B-cells for which standard care involves the inhibition of the proteasome. All clinically used proteasome inhibitors, including the chemotherapeutic drug bortezomib, target the catalytic active sites of the proteasome and inhibit protein proteolysis by competing with substrate binding. However, nearly all (~97%) patients become intolerant or resistant to treatments within a few years, after which the average survival time is less than one year. We describe herein the inhibition of the human proteasome via a non-competitive mechanism by the imidazoline scaffold, TCH-13. Consistent with a mechanism distinct from competitive inhibitors, TCH-013 acts additively with and overcomes resistance to bortezomib. Importantly, TCH-013 induces apoptosis a panel of myeloma and leukemia cell lines, but in contrast, normal lymphocytes, primary bone marrow stromal cells and macrophages are resistant to its cytotoxic effects. TCH-013 was equally effective in blocking MM cell growth in co-cultures of MM cells with hBMSC isolated from CD138 negative BM samples of MM patients. The cellular activity translated well in vivo where TCH-013 delayed tumor growth in an MM xenograft model to a similar extent as bortezomib.

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“…33,34 It was reported that oral administration of NF-κB inhibitors could attenuate CIA. 35 In recent years, there has been extensive research on the connection between inflammation and cancer; inhibition of NF-κB could inhibit inflammation and reduce the incidence of cancer. 36,37 It was reported that garcinol possesses antiinflammatory and anticancer activities.…”

Section: ■ Discussionmentioning

confidence: 99%

Immune Regulation and Anti-inflammatory Effects of Isogarcinol Extracted from Garcinia mangostana L. against Collagen-Induced Arthritis

Zhou

Wang

et al. 2014

J. Agric. Food Chem.

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Isogarcinol is a natural compound that we extracted from Garcinia mangostana L., and we were the first to report that it is a new immunosuppressant. In the present study, we investigated the immune regulation and anti-inflammatory effects of isogarcinol on collagen-induced arthritis (CIA) and explored its potential mechanism in the treatment of rheumatoid arthritis. The oral administration of isogarcinol significantly reduced clinical scores, alleviated cartilage and bone erosion, and reduced the levels of serum inflammatory cytokines in CIA mice. Isogarcinol inhibited xylene-induced mouse ear edema in vivo. In vitro, isogarcinol decreased iNOS and COX-2 mRNA expression and NO content by inhibiting NF-κB expression. Furthermore, isogarcinol decreased the activity of NFAT and inhibited IL-2 expression. The mechanism of action of isogarcinol is associated with down-regulation of both autoimmune and inflammatory reactions.

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Attenuation of collagen-induced arthritis by orally available imidazoline-based NF-κB inhibitors

Cited by 6 publications

References 19 publications

Inhibition of the Human Proteasome by Imidazoline Scaffolds

Inhibition of the Human Proteasome by Imidazoline Scaffolds

Noncompetitive Modulation of the Proteasome by Imidazoline Scaffolds Overcomes Bortezomib Resistance and Delays MM Tumor Growth in Vivo

Immune Regulation and Anti-inflammatory Effects of Isogarcinol Extracted from Garcinia mangostana L. against Collagen-Induced Arthritis

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