Small Molecules Targeting the RNA-Binding Protein HuR Inhibit Tumor Growth in Xenografts.

The RNA-binding protein Hu antigen R (HuR) is a post-transcriptional regulator critical in several types of diseases, including cancer, making it a promising therapeutic target. We have identified small-molecule inhibitors of HuR through a screening approach used in combination with fragment analysis. A total of 36 new compounds originating from fragment linking or structural optimization were studied to establish structure-activity relationships in the set. Two top inhibitors, 1c and 7c, were further validated by binding assays and cellular functional assays. Both block HuR function by directly binding to the RNA-binding pocket, inhibit cancer cell growth dependence of HuR, and suppress cancer cell invasion. Intraperitoneal administration of inhibitor 1c inhibits tumor growth as a single agent and shows a synergistic effect in combination with chemotherapy docetaxel in breast cancer xenograft models. Mechanistically, 1c interferes with the HuR-TGFB/THBS1 axis.

Cognitive outcome following bilateral subthalamic nucleus deep brain stimulation for Parkinson's disease-a comparative observational study in Indian patients.

BACKGROUND: Deep brain stimulation (DBS) of the subthalamic nucleus (STN) improves motor symptoms and motor complications of Parkinson's disease (PD). The intervention is expected to result in some cognitive changes, the nature of which is not uniform across the studies which have reported them. PD itself is associated with progressive cognitive decline and hence longitudinal follow-up studies with medically managed control group of patients are needed to explore the cognitive deficits attributable to DBS. METHODS: We conducted a prospective comparative observational study to assess the effects of bilateral STN DBS on cognition. Cognitive functions were assessed at baseline and after a minimum of two years after surgery, and compared with baseline and follow-up assessments in patients on medical management alone. RESULTS: Thirty-four patients with PD who underwent bilateral STN DBS and thirty-four medically managed patients participated in the study. At a mean follow-up of around 33 months, we found a significant decline in verbal fluency scores in the DBS group compared to those on medical management alone (1.15 ± 1.23 vs 0.59 ± 0.93, p = 0.034) and a trend for decline was noted in digit span test. There was no difference in the performance in tests addressing other cognitive domains, or tests of global cognitive function. No patient developed dementia. Motor functions and activities of daily living (ADL) were significantly better in the surgical group. CONCLUSION: STN DBS results in minor deficits in executive functions, particularly verbal fluency. These may be inconsequential, considering the marked improvement in motor functions and ADL.

An RNA-Binding Protein, Hu-antigen R, in Pancreatic Cancer Epithelial to Mesenchymal Transition, Metastasis, and Cancer Stem Cells.

Pancreatic cancer has poor prognosis and treatment outcomes due to its highly metastatic nature and resistance to current treatments. The RNA-binding protein (RBP) Hu-antigen R (HuR) is a central player in posttranscriptional regulation of cancer-related gene expression, and contributes to tumorigenesis, tumor growth, metastasis, and drug resistance. HuR has been suggested to regulate pancreatic cancer epithelial-to-mesenchymal transition (EMT), but the mechanism was not well understood. Here, we further elucidated the role HuR plays in pancreatic cancer cell EMT, and developed a novel inhibitor specifically interrupting HuR-RNA binding. The data showed that HuR binds to the 3'-UTR of the mRNA of the transcription factor Snail, resulting in stabilization of Snail mRNA and enhanced Snail protein expression, thus promoted EMT, metastasis, and formation of stem-like cancer cells (CSC) in pancreatic cancer cells. siRNA silencing or CRISPR/Cas9 gene deletion of HuR inhibited pancreatic cancer cell EMT, migration, invasion, and inhibited CSCs. HuR knockout cells had dampened tumorigenicity in immunocompromised mice. A novel compound KH-3 interrupted HuR-RNA binding, and KH-3 inhibited pancreatic cancer cell viability, EMT, migration/invasion in vitro KH-3 showed HuR-dependent activity and inhibited HuR-positive tumor growth and metastasis in vivo.

Synthesis of the Nonribosomal Peptide Phevalin and Analogs.

Phevalin, a cyclic nonribosomal peptide produced by Staphylococcus aureus, has intriguing biological properties. A synthetic route to access phevalin and similar pyrazinone natural products tyrvalin, leuvalin, phileucin, and a few synthetic analogs is described. The reaction sequence involves a one-pot carbamate deprotection/imine formation/aerobic oxidation to form the pyrazinone-containing products.

Repurposing of a drug scaffold: Identification of novel sila analogues of rimonabant as potent antitubercular agents.

The structural similarity between an MmpL3 inhibitor BM212, and a cannabinoid receptor modulator rimonabant, prompted us to investigate the anti-tubercular activity of rimonabant and its analogues. Further optimization, particularly through incorporation of silicon into the scaffold, resulted in new compounds with significant improvement in anti-tubercular activity against Mycobacterium tuberculosis (H37Rv). The sila analogue 18a was found to be the most potent antimycobacterial compound (MIC, 31 ng/mL) from this series with an excellent selectivity index.