0415 is an ikk beta inhibitor pre-clinical candidate
anyone familiar with the above? thanks.
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Bioorg Med Chem Lett. 2003 Jul 21;13(14):2419-22. Related Articles, Links
Novel IKK inhibitors: beta-carbolines.
Castro AC, Dang LC, Soucy F, Grenier L, Mazdiyasni H, Hottelet M, Parent L, Pien C, Palombella V, Adams J.
Millennium Pharmaceuticals Inc., 35 Landsdowne Street, 02139, Cambridge, MA, USA.
Inhibitors of IkappaB kinase (IKK) have long been sought as specific regulators of NF-kappaB. A screening effort of the endogenous IKK complex allowed us to identify 5-bromo-6-methoxy-beta-carboline as a nonspecific IKK inhibitor. Optimization of this beta-carboline natural product derivative resulted in a novel class of selective IKK inhibitors with IC(50)s in the nanomolar range. In addition, we show that one of these beta-carboline analogues inhibits the phosphorylation of IkappaBalpha and subsequent activation of NF-kappaB in whole cells, as well as blocking TNF-alpha release in LPS-challenged mice.
PMID: 12824047 [PubMed - indexed for MEDLINE]
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Oncogene advance online publication 19 September 2005; doi: 10.1038/sj.onc.1209066
Effects of IKK inhibitor PS1145 on NF- B function, proliferation, apoptosis and invasion activity in prostate carcinoma cells
A Yemelyanov1,4, A Gasparian2,4, P Lindholm1, L Dang3, J W Pierce3,5, F Kisseljov2, A Karseladze2 and I Budunova1
1. 1Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
2. 2NN Blokhin Russian Cancer Research Center, Moscow, Russia
3. 3Millennium Pharmaceuticals Inc., Cambridge, MA, USA
Correspondence: Dr I Budunova, Department of Dermatology, Northwestern University, Ward Building 9-332, 303 East Chicago Avenue, Chicago, IL 60611, USA. E-mail: i-budunova@northwestern.edu
4These two authors contributed equally to this work.
5Current address: Merck Research Laboratories Boston, Boston, MA, USA.
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Abstract
A key antiapoptotic transcription factor, nuclear factor kappa-B (NF- B), is known to be critically important for tumor cell growth, angiogenesis and development of metastatic lesions. We and others showed previously that NF- B transcription factor was constitutively activated in androgen-independent prostate carcinoma (PC) cell lines due to the upregulated activity of inhibitor of NF- B kinases (IKK). In this work, using luciferase assay, electrophoretic mobility shift assay and Northern blot analysis of expression of endogenous B-responsive genes, we demonstrate that a novel highly specific small-molecule IKK inhibitor, PS1145, efficiently inhibited both basal and induced NF- B activity in PC cells. We found that PS1145 induced caspase 3/7-dependent apoptosis in PC cells and significantly sensitized PC cells to apoptosis induced by tumor necrosis factor alpha. We also showed that PS1145 inhibited PC cell proliferation. Effects of PS1145 on proliferation and apoptosis correlated with inhibition of interleukin (IL)-6, cyclin D1, D2, inhibitor of apoptosis (IAP)-1 and IAP-2 gene expression and decreased IL-6 protein level. In addition, we found that incubation with PS1145 inhibited the invasion activity of highly invasive PC3-S cells in invasion chamber assay in a dose-dependent manner. Overall, this study provides the framework for development of a novel therapeutic approach targeting NF- B transcription factor to treat advanced PC.
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1: J Pharmacol Exp Ther. 2005 Oct;315(1):382-8. Epub 2005 Jul 11.
Collagen and Aggrecan Degradation Is Blocked in Interleukin-1-Treated Cartilage Explants by an Inhibitor of I{kappa}B Kinase through Suppression of Metalloproteinase Expression.
Pattoli MA, Macmaster JF, Gregor KR, Burke JR.
Bristol-Myers Squibb, P.O. Box 4000, Princeton, NJ 08543. james.burke@bms.com.
It has previously been shown that BMS-345541 [4(2'-aminoethyl)amino-1,8-dimethylimidazo(1,2-a)quinoxaline], a highly-selective inhibitor of IkappaB kinase (IKK), blocks both inflammation and joint destruction in murine collagen-induced arthritis. Although this agent has been shown to inhibit nuclear factor-kappaB-dependent cytokine expression in mice, we examined whether the inhibitor directly inhibits cytokine-driven metalloproteinase expression and cartilage degradation. In SW-1353 human chondrosarcoma cells, BMS-345541 inhibited interleukin-1 (IL-1)-dependent expression of matrix metalloproteinase (MMP)-1, MMP-3, and MMP-13 in a concentration-dependent manner. IL-1 treatment failed to induce and BMS-345541 did not inhibit the expression of aggrecanases ADAMTS-4 (a disintegrin and metalloproteinase domain with thrombospondin motif) and ADAMTS-5, as well as the tissue inhibitor of metalloproteinase-3. In bovine cartilage explant cultures stimulated with IL-1 to induce aggrecan and collagen degradation over 3 weeks of culture, BMS-345541 was effective in inhibiting the degradation of both aggrecan and collagen. Secreted ADAMTS-4 was not inhibited by BMS-345541 in these explants, whereas ADAMTS-5 secretion was blocked in the same concentration range that inhibited aggrecan degradation. The ability of the IKK inhibitor to block aggrecan and collagen degradation through suppression of metalloproteinase expression, coupled with its ability to block inflammatory cytokine production, shows IKK to be a promising target for the development of novel agents to treat arthritic diseases.
PMID: 16009742 [PubMed - in process] |
