A Small Compound Targeting Prohibitin with Potential Interest for Cognitive Deficit Rescue in Aging mice and Tau Pathology Treatment.

Neurodegenerative diseases, including Alzheimer's and Parkinson's disease, are characterized by increased protein aggregation in the brain, progressive neuronal loss, increased inflammation, and neurogenesis impairment. We analyzed the effects of a new purine derivative drug, PDD005, in attenuating mechanisms involved in the pathogenesis of neurodegenerative diseases, using both in vivo and in vitro models. We show that PDD005 is distributed to the brain and can rescue cognitive deficits associated with aging in mice. Treatment with PDD005 prevents impairment of neurogenesis by increasing sex-determining region Y-box 2, nestin, and also enhances synaptic function through upregulation of synaptophysin and postsynaptic density protein 95. PDD005 treatment also reduced neuro-inflammation by decreasing interleukin-1ß expression, activation of astrocytes, and microglia. We identified prohibitin as a potential target in mediating the therapeutic effects of PDD005 for the treatment of cognitive deficit in aging mice. Additionally, in the current study, glycogen synthase kinase appears to attenuate tau pathology.

The toll-like receptor agonist imiquimod is active against prions.

Using a yeast-based assay, a previously unsuspected antiprion activity was found for imiquimod (IQ), a potent Toll-like receptor 7 (TLR7) agonist already used for clinical applications. The antiprion activity of IQ was first detected against yeast prions [PSI (+) ] and [URE3], and then against mammalian prion both ex vivo in a cell-based assay and in vivo in a transgenic mouse model for prion diseases. In order to facilitate structure-activity relationship studies, we conducted a new synthetic pathway which provides a more efficient means of producing new IQ chemical derivatives, the activity of which was tested against both yeast and mammalian prions. The comparable antiprion activity of IQ and its chemical derivatives in the above life forms further emphasizes the conservation of prion controlling mechanisms throughout evolution. Interestingly, this study also demonstrated that the antiprion activity of IQ and IQ-derived compounds is independent from their ability to stimulate TLRs. Furthermore, we found that IQ and its active chemical derivatives inhibit the protein folding activity of the ribosome (PFAR) in vitro.

Inhibition of NF-κB-mediated signaling by the cyclin-dependent kinase inhibitor CR8 overcomes prosurvival stimuli to induce apoptosis in chronic lymphocytic leukemia cells.

PURPOSE: Chronic lymphocytic leukemia (CLL) is currently incurable with standard chemotherapeutic agents, highlighting the need for novel therapies. Overcoming proliferative and cytoprotective signals generated within the microenvironment of lymphoid organs is essential for limiting CLL progression and ultimately developing a cure. EXPERIMENTAL DESIGN: We assessed the potency of cyclin-dependent kinase (CDK) inhibitor CR8, a roscovitine analog, to induce apoptosis in primary CLL from distinct prognostic subsets using flow cytometry-based assays. CLL cells were cultured in in vitro prosurvival and proproliferative conditions to mimic microenvironmental signals in the lymphoid organs, to elucidate the mechanism of action of CR8 in quiescent and proliferating CLL cells using flow cytometry, Western blotting, and quantitative real-time PCR. RESULTS: CR8 was 100-fold more potent at inducing apoptosis in primary CLL cells than roscovitine, both in isolated culture and stromal-coculture conditions. Importantly, CR8 induced apoptosis in CD40-ligated CLL cells and preferentially targeted actively proliferating cells within these cultures. CR8 treatment induced downregulation of the antiapoptotic proteins Mcl-1 and XIAP, through inhibition of RNA polymerase II, and inhibition of NF-κB signaling at the transcriptional level and through inhibition of the inhibitor of IκB kinase (IKK) complex, resulting in stabilization of IκBα expression. CONCLUSIONS: CR8 is a potent CDK inhibitor that subverts pivotal prosurvival and proproliferative signals present in the tumor microenvironment of CLL patient lymphoid organs. Our data support the clinical development of selective CDK inhibitors as novel therapies for CLL.

Cyclin-dependent kinase inhibitors: a survey of recent patent literature.

IMPORTANCE OF THE FIELD: Abnormalities in protein phosphorylation by cyclin-dependent kinases (CDKs) have been observed in numerous major human diseases, which has strongly encouraged the search for pharmacological inhibitors. Almost 10 years after the first compounds entered clinical studies, numerous CDK inhibitors with differing selectivity profiles are now undergoing preclinical and clinical evaluation. Nevertheless, these intensive searches have not yet resulted in drug approvals. AREAS COVERED IN THIS REVIEW: This paper reviews patent activity associated with these efforts during the 2005 - 2008 period. WHAT THE READER WILL GAIN: Readers will rapidly obtain an overview of the majority of CDK inhibitor scaffolds; they will discover which companies are the main players in the field and acquire information on products that have reached the clinical phases. TAKE HOME MESSAGE: In most cases, applications have been claimed in the field of cancer; however, potential applications of CDK inhibitors in other therapeutic areas are regularly reported and could herald therapeutic introduction over the next few years.

Procedure for identification and characterization of drugs efficient against mammalian prion: from a yeast-based antiprion drug screening assay to in vivo mouse models.

Prion diseases are fatal and incurable infectious neurodegenerative disorders affecting humans and other mammals. Prions are composed essentially if not solely of PrP(Sc), a misfolded form of the host-encoded PrP protein. PrP(Sc) catalyzes the transconformation of the normal endogenous PrP (PrP(C)) into more PrP(Sc). Prion replication thus corresponds to the propagation of an altered folding state of PrP. Several prion proteins have also been identified in the simple model organism Saccharomyces cerevisiae. Yeast prion-based screening assays have allowed identification of drugs active against mammalian prions, thus revealing the existence of common prion propagation mechanisms conserved from yeast to human. To identify these conserved targets, antiprion compounds isolated in yeast can be used as baits in reverse screening strategies. Once identified, these targets could in turn lead to the development of mechanism-based cell-free antiprion screening assays. A reverse screening procedure has been performed for 6AP and GA, two antiprion compounds isolated using a yeast-based assay. Protein folding activity of the large ribosomal RNA was found to be a physical and a functional target of both 6AP and GA therefore suggesting that this activity of the ribosome may constitute a novel mechanism involved in prion propagation and, as a consequence, a new screening target.

A yeast-based assay to isolate drugs active against mammalian prions.

Recently, we have developed a yeast-based (Saccharomyces cerevisiae) assay to isolate drugs active against mammalian prions. The initial assumption was that mechanisms controlling prion appearance and/or propagation could be conserved from yeast to human, as it is the case for most of the major cell biology regulatory mechanisms. Indeed, the vast majority of drugs we isolated as active against both [PSI(+)] and [URE3] budding yeast prions turned out to be also active against mammalian prion in three different mammalian cell-based assays. These results strongly argue in favor of common prion controlling mechanisms conserved in eukaryotes, thus validating our yeast-based assay and also the use of budding yeast to identify antiprion compounds and to study the prion world.