The PDE10A Inhibitor TAK-063 Reverses Sound-Evoked EEG Abnormalities in a Mouse Model of Fragile X Syndrome.

Fragile X syndrome (FXS) is a genetic neurodevelopmental syndrome characterized by increased anxiety, repetitive behaviors, social communication deficits, delayed language development, and abnormal sensory processing. Recently, we have identified electroencephalographic (EEG) biomarkers that are conserved between the mouse model of FXS (Fmr1 KO mice) and humans with FXS. In this study, we test a specific candidate mechanism for engagement of multielectrode array (MEA) EEG biomarkers in the FXS mouse model.

The Potential of MLN3651 in Combination with Selumetinib as a Treatment for Merlin-Deficient Meningioma.

Meningioma is the most common primary intracranial tumour, and surgical resection is the main therapeutic option. Merlin is a tumour suppressor protein that is frequently mutated in meningioma. The activity of the E3 ubiquitin ligase complex, CRL4-DCAF1, and the Raf/MEK/ERK scaffold protein Kinase suppressor of Ras 1 (KSR1) are upregulated in Merlin-deficient tumours, which drives tumour growth.

Novel HDAC6 Inhibitors Increase Tubulin Acetylation and Rescue Axonal Transport of Mitochondria in a Model of Charcot-Marie-Tooth Type 2F.

Disruption of axonal transport causes a number of rare, inherited axonopathies and is heavily implicated in a wide range of more common neurodegenerative disorders, many of them age-related. Acetylation of α-tubulin is one important regulatory mechanism, influencing microtubule stability and motor protein attachment. Of several strategies so far used to enhance axonal transport, increasing microtubule acetylation through inhibition of the deacetylase enzyme histone deacetylase 6 (HDAC6) has been one of the most effective.

Design, synthesis and biological evaluation of novel inosine 5'-monophosphate dehydrogenase (IMPDH) inhibitors.

This study is based on our attempts to further explore the structure-activity relationship (SAR) of VX-148 (3) in an attempt to identify inosine 5'-mono-phosphate dehydrogenase (IMPDH) inhibitors superior to mycophenolic acid. A five-point pharmacophore developed using structurally diverse, known IMPDH inhibitors guided further design of novel analogs of 3. Several conventional as well as novel medicinal chemistry strategies were tried.

Virtual and experimental high-throughput screening (HTS) in search of novel inosine 5'-monophosphate dehydrogenase II (IMPDH II) inhibitors.

IMPDH (Inosine 5'-monophosphate dehydrogenase) catalyzes a rate-limiting step in the de novo biosynthesis of guanine nucleotides. IMPDH inhibition in sensitive cell types (e.g.

Designing HIV integrase inhibitors--shooting the last arrow.

The arsenal of drugs in the fight against AIDS is rapidly diminishing as the HIV becomes resistant to the available reverse transcriptase and protease inhibitors. After killing millions all over the world, the virus is still on the rampage and hence the pharmaceutical industry is resorting to the development of inhibitors of integrase. This seems to be the last arrow in the quiver of potential drug leads to combat the deadly infection.

Correlation between inactive cathepsin D expression and retinal changes in mcd2/mcd2 transgenic mice.

Purpose: To investigate the correlation between the presence of the inactive cathepsin D (CatD) and retinal changes in mcd2/mcd2 transgenic mice.

Methods: Computational modeling was used to examine whether CatD mutants maintain competitive substrate binding. D407 cells were transfected with pcDNACatDM1 or pcDNACatDM2, containing procathepsin D (pro-CatD) with 6-bp (CatDM1) or 12-bp (CatDM2) deletions, respectively, flanking the pro-CatD cleavage site, and the aspartic protease activity of the transfected cells was measured.

De novo design and synthesis of HIV-1 integrase inhibitors.

Existing AIDS therapies are out of reach for most HIV-infected people in developing countries and, where available, they are limited by their toxicity and their cost. New anti-HIV agents are needed urgently to combat emerging viral resistance and reduce the side effects associated with currently available drugs. Toward this end, LeapFrog, a de novo drug design program was used to design novel, potent, and selective inhibitors of HIV-1 integrase.

3D-QSAR and molecular modeling of HIV-1 integrase inhibitors.

Three-dimensional quantitative structure-activity relationship (3D QSAR) methods were applied on a series of inhibitors of HIV-1 integrase with respect to their inhibition of 3'-processing and 3'-end joining steps in vitro. The training set consisted of 27 compounds belonging to the class of thiazolothiazepines. The predictive ability of each model was evaluated using test set I consisting of four thiazolothiazepines and test set II comprised of seven compounds belonging to an entirely different structural class of coumarins.

QSAR of HIV-1 integrase inhibitors by genetic function approximation method.

Quantitative structure--activity relationship (QSAR) paradigm, using genetic function approximation (GFA) technique was used to examine the correlations between the calculated physicochemical descriptors and the in vitro activities (3'-processing and 3'-strand transfer inhibition) of a series of human immunodeficiency virus type 1 (HIV-1) integrase inhibitors. Depending on the chemical structure, all molecules were divided into two classes---catechols and noncatechols. Eighty-one molecules were used in the present study and they were divided into training set and test set.