Emerging classes of protein–protein interaction inhibitors and new tools for their development

Pagliaro, L; Felding, Jakob; Audouze, Karine; Nielsen, Søren; Terry, Robert; Krog-Jensen, Christian; Butcher, Steven P.

doi:10.1016/j.cbpa.2004.06.006

Cited by 160 publications

(128 citation statements)

References 49 publications

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“…Therefore, the development of new strategies to modulate Id-1 expression/functional activity is needed. A range of small molecules that target the molecular pathology of cancer are now being developed, and a significant number of them are being tested in ongoing human clinical trials (17). We propose that the use of CBD, as an inhibitor of Id-1, represents a novel strategy to treat breast cancer.…”

Section: Discussionmentioning

confidence: 99%

Cannabidiol as a novel inhibitor of Id-1 gene expression in aggressive breast cancer cells

McAllister

Christian²,

Horowitz³

et al. 2007

Molecular Cancer Therapeutics

199

169

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Invasion and metastasis of aggressive breast cancer cells is the final and fatal step during cancer progression, and is the least understood genetically. Clinically, there are still limited therapeutic interventions for aggressive and metastatic breast cancers available. Clearly, effective and nontoxic therapies are urgently required. Id-1, an inhibitor of basic helix-loop-helix transcription factors, has recently been shown to be a key regulator of the metastatic potential of breast and additional cancers. Using a mouse model, we previously determined that metastatic breast cancer cells became significantly less invasive in vitro and less metastatic in vivo when Id-1 was down-regulated by stable transduction with antisense Id-1. It is not possible at this point, however, to use antisense technology to reduce Id-1 expression in patients with metastatic breast cancer. Here, we report that cannabidiol (CBD), a cannabinoid with a low-toxicity profile, could down-regulate Id-1 expression in aggressive human breast cancer cells. The CBD concentrations effective at inhibiting Id-1 expression correlated with those used to inhibit the proliferative and invasive phenotype of breast cancer cells. CBD was able to inhibit Id-1 expression at the mRNA and protein level in a concentration-dependent fashion. These effects seemed to occur as the result of an inhibition of the Id-1 gene at the promoter level. Importantly, CBD did not inhibit invasiveness in cells that ectopically expressed Id-1. In conclusion, CBD represents the first nontoxic exogenous agent that can significantly decrease Id-1 expression in metastatic breast cancer cells leading to the down-regulation of tumor aggressiveness. [Mol Cancer Ther 2007;6(11):2921 -7]

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Section: Discussionmentioning

confidence: 99%

Cannabidiol as a novel inhibitor of Id-1 gene expression in aggressive breast cancer cells

McAllister

Christian²,

Horowitz³

et al. 2007

Molecular Cancer Therapeutics

199

169

View full text Add to dashboard Cite

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“…Further proof-of-concept, suggesting that alteration in protein conformation within cells in vitro and in vivo may be a valid approach to alter protein function, comes from studies of Fabry disease (161,162). A recent review summarizes the use of small molecules to modulate the structure and function of various proteins of biological importance (163).…”

Section: New Therapeutic Approaches: Small Molecules To Block Domain mentioning

confidence: 99%

Apolipoprotein E4: A causative factor and therapeutic target in neuropathology, including Alzheimer’s disease

Mahley

Weisgraber

Huang

2006

Proc. Natl. Acad. Sci. U.S.A.

834

801

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The premise of this review is that apolipoprotein (apo) E4 is much more than a contributing factor to neurodegeneration. ApoE has critical functions in redistributing lipids among CNS cells for normal lipid homeostasis, repairing injured neurons, maintaining synaptodendritic connections, and scavenging toxins. In multiple pathways affecting neuropathology, including Alzheimer's disease, apoE acts directly or in concert with age, head injury, oxidative stress, ischemia, inflammation, and excess amyloid ␤ peptide production to cause neurological disorders, accelerating progression, altering prognosis, or lowering age of onset. We envision that unique structural features of apoE4 are responsible for apoE4-associated neuropathology. Although the structures of apoE2, apoE3, and apoE4 are in dynamic equilibrium, apoE4, which is detrimental in a variety of neurological disorders, is more likely to assume a pathological conformation. Importantly, apoE4 displays domain interaction (an interaction between the N-and C-terminal domains of the protein that results in a compact structure) and molten globule formation (the formation of stable, reactive intermediates with potentially pathological activities). In response to CNS stress or injury, neurons can synthesize apoE. ApoE4 uniquely undergoes neuron-specific proteolysis, resulting in bioactive toxic fragments that enter the cytosol, alter the cytoskeleton, disrupt mitochondrial energy balance, and cause cell death. Our findings suggest potential therapeutic strategies, including the use of ''structure correctors'' to convert apoE4 to an ''apoE3-like'' molecule, protease inhibitors to prevent the generation of toxic apoE4 fragments, and ''mitochondrial protectors'' to prevent cellular energy disruption. mitochondria ͉ neurodegeneration ͉ cytoskeleton ͉ protein folding A polipoprotein (apo) E plays a fundamental role in the maintenance and repair of neurons, but its three isoforms differ in their abilities to accomplish these critical tasks (1-3). ApoE4 is associated with a wide variety of neuropathological processes. We hypothesize that different insults associated with a variety of disorders, in concert with apoE4, can lead to neuropathology. We believe that those processes are mediated by the cellular origin of apoE (astrocytes, neurons, or microglia), the nature of various injurious factors (''second hits''), and the structure of apoE4. Thus, understanding the structure and function of the apoE isoforms will yield new strategies for treating neuropathologies.Although apoE is involved in many neuropathologies, we will focus on its role in Alzheimer's disease (AD). We will consider the unique structural features that distinguish apoE4 from apoE3 and apoE2, the sites of synthesis and normal roles of apoE in the nervous system, and the pathological roles of apoE4 with or without amyloid ␤ (A␤) peptide. The evidence suggests that apoE4 is considerably more than a simple contributing factor in AD pathogenesis. ApoE and NeuropathologyApoE4's involvement in neuropathology is we...

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“…The discovery of interaction hotspots indicated that smaller -and therefore more druggable -sites might exist within PPI interfaces Wells and McClendon 2007). Analysis of PPI surfaces has established general trends in composition, suggesting branched hydrophobic side chains and aromatic residues are preferred, with lower percentages observed for charged and polar groups Pagliaro et al 2004;Fry 2006). However, the context of polar groups can be critical for establishing affinity and specificity, as with the Glu 62 buried salt-bridge in the IL2:IL-2Ra and IL-2: SP4206 complexes.…”

Section: Inhibitable Surface Epitopesmentioning

confidence: 99%

Small-Molecule Inhibitors of IL-2/IL-2R: Lessons Learned and Applied

Wilson

Arkin

2010

Current Topics in Microbiology and Immunology

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Emerging classes of protein–protein interaction inhibitors and new tools for their development

Cited by 160 publications

References 49 publications

Cannabidiol as a novel inhibitor of Id-1 gene expression in aggressive breast cancer cells

Cannabidiol as a novel inhibitor of Id-1 gene expression in aggressive breast cancer cells

Apolipoprotein E4: A causative factor and therapeutic target in neuropathology, including Alzheimer’s disease

Small-Molecule Inhibitors of IL-2/IL-2R: Lessons Learned and Applied

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