Structural–activity relationship study of highly-functionalized imidazolines as potent inhibitors of nuclear transcription factor-κB mediated IL-6 production

Kahlon, Daljinder K.; Lansdell, Theresa A.; Fisk, Jason S.; Tepe, Jetze J.

doi:10.1016/j.bmc.2009.03.002

Cited by 34 publications

(12 citation statements)

References 50 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Cells were treated with the inhibitory peptide or an inactive control. 1 μM TCH 021, a novel imidazoline, inhibits NF‐kB gene transcription by modulating IkB degradation and subsequently inhibiting DNA binding (Kahlon et al., 2009; Peddibhotla and Tepe, 2004; Sharma et al., 2004). All inhibitors were diluted in sterile PBS, DMSO, or water and used for 24 h unless stated.…”

Section: Methodsmentioning

confidence: 99%

Increased extracellular pressure stimulates tumor proliferation by a mechanosensitive calcium channel and PKC‐β

et al. 2014

Self Cite

View full text Add to dashboard Cite

Large tumors exhibit high interstitial pressure heightened by growth against the constraining stroma. Such pressures could stimulate tumor proliferation via a mechanosensitive ion channel. We studied the effects of 0–80 mm Hg increased extracellular pressure for 24 hours on proliferation of SW620, Caco-2, and CT-26 colon; MCF-7 breast; and MLL and PC3 prostate cancer cells, and delineated its mechanism in SW620 cells with specific inhibitors and siRNA. Finally, we compared NF-kB, phospho-IkB and cyclin D1 immunoreactivity in the high pressure centers and low pressure peripheries of human tumors. Pressure stimulated proliferation in all cells. Pressure-driven SW620 proliferation required calcium influx via the T-type Ca2+ channel Cav3.3, which stimulated PKC-β to invoke the IKK-IkB-NF-kB pathway to increase proliferation and S-phase fraction. The mitotic index and immunoreactivity of NF-kB, phospho-IkB, and cyclin D1 in the center of 28 large human colon, lung, and head and neck tumors exceeded that in tumor peripheries. Extracellular pressure increases [Ca2+]i via Cav3.3, driving a PKC-β-IKK-IkB-NF-kB pathway that stimulates cancer cell proliferation. Rapid proliferation in large stiff tumors may increase intratumoral pressure, activating this pathway to stimulate further proliferation in a feedback cycle that potentiates tumor growth. Targeting this pathway may inhibit proliferation in large unresectable tumors.

show abstract

Section: Methodsmentioning

confidence: 99%

Increased extracellular pressure stimulates tumor proliferation by a mechanosensitive calcium channel and PKC‐β

et al. 2014

Self Cite

View full text Add to dashboard Cite

show abstract

“…Imidazolines are an important class of compounds that are found in various natural and synthetic bioactive molecules [ 257 , 258 ]. This class of compounds displays a wide range of biological activities including proteasome and NF- κ B modulation [ 259 , 260 , 261 ], and therapeutic significance such as antifungi [ 262 ], antitumor [ 263 ], antihelminthics [ 264 ], antihyperglycemic [ 265 ], and antihypertensive activity [ 266 ].…”

Section: Small Molecule Enhancers Of 20s Proteasome Activitymentioning

confidence: 99%

Advances in Proteasome Enhancement by Small Molecules

George

Tepe

2021

Biomolecules

Self Cite

View full text Add to dashboard Cite

The proteasome system is a large and complex molecular machinery responsible for the degradation of misfolded, damaged, and redundant cellular proteins. When proteasome function is impaired, unwanted proteins accumulate, which can lead to several diseases including age-related and neurodegenerative diseases. Enhancing proteasome-mediated substrate degradation with small molecules may therefore be a valuable strategy for the treatment of various neurodegenerative diseases such as Parkinson’s, Alzheimer’s, and Huntington’s diseases. In this review, we discuss the structure of proteasome and how proteasome’s proteolytic activity is associated with aging and various neurodegenerative diseases. We also summarize various classes of compounds that are capable of enhancing, directly or indirectly, proteasome-mediated protein degradation.

show abstract

“…17 We evaluated the use of 20S proteasome enhancement for its therapeutic potential in cell culture and in vivo, using the 20S proteasome enhancer, TCH-165. TCH-165 is part of a privileged class of imidazolinebased scaffolds, [18][19][20][21][22][23][24] and is one of the few known molecules shown to enhances 20S mediated proteolysis nearly 10 fold (i.e. 1000%) by favoring a proteolytically active, open-gate 20S proteasome subcomplex.…”

Section: Introductionmentioning

confidence: 99%

Enhancing c-MYC degradation via 20S proteasome activation inducesin vivoanti-tumor efficacy

Njomen

Lansdell

Vanecek

et al. 2020

Preprint

Self Cite

View full text Add to dashboard Cite

Enhancing proteasome activity is a potential new therapeutic strategy to prevent the accumulation of aberrant high levels of protein that drive the pathogenesis of many diseases. Herein, we examine the use of small mole-cules to activate the 20S proteasome to reduce aberrant signaling by the undruggable oncoprotein c-MYC, to treat c-MYC driven oncogenesis. Overexpression of c-MYC is found in more than 50% of all human cancer but remains undruggable because of its highly dynamic intrinsically disordered 3-D conformation, which renders traditional therapeutic strategies largely ineffective. We demonstrate herein that small molecule activation of the 20S proteasome targets dysregulated intrinsically disordered proteins (IDPs), including c-MYC, and reduces can-cer growth in vitro and in vivo models of multiple myeloma, and is even effective in bortezomib resistant cells and unresponsive patient samples. Genomic analysis of various cancer pathways showed that proteasome activation results in downregulation of many c-MYC target genes. Moreover, proteasome enhancement was well tolerated in mice and dogs. These data support the therapeutic potential of 20S proteasome activation in tar-geting IDP-driven proteotoxic disorders, including cancer, and demonstrate that this new therapeutic strategy is well tolerated in vivo.

show abstract

Structural–activity relationship study of highly-functionalized imidazolines as potent inhibitors of nuclear transcription factor-κB mediated IL-6 production

Cited by 34 publications

References 50 publications

Increased extracellular pressure stimulates tumor proliferation by a mechanosensitive calcium channel and PKC‐β

Increased extracellular pressure stimulates tumor proliferation by a mechanosensitive calcium channel and PKC‐β

Advances in Proteasome Enhancement by Small Molecules

Enhancing c-MYC degradation via 20S proteasome activation inducesin vivoanti-tumor efficacy

Contact Info

Product

Resources

About