High-throughput small molecule screen identifies inhibitors of aberrant chromatin accessibility

Transcriptional regulators lacking enzymatic activity or binding pockets with targetable molecular features have typically been considered “undruggable,” and a reductionist approach based on identification of their molecular targets has largely failed. We have demonstrated that the Ewing sarcoma chimeric transcription factor, EWSR1-FLI1, maintains accessible chromatin at disease-specific regions. We adapted formaldehyde-assisted isolation of regulatory elements (FAIRE), an assay for accessible chromatin, to screen an epigenetically targeted small molecule library for compounds that reverse the disease-associated signature. This approach can be applied broadly for discovery of chromatin-based developmental therapeutics and offers significant advantages because it does not require the selection of a single molecular target. Using this approach, we identified a specific class of compounds with therapeutic potential

SCYX-7158, an Orally-Active Benzoxaborole for the Treatment of Stage 2 Human African Trypanosomiasis

Human African trypanosomiasis (HAT) is caused by infection with the parasite Trypanosoma brucei and is an important public health problem in sub-Saharan Africa. New, safe, and effective drugs are urgently needed to treat HAT, particularly stage 2 disease where the parasite infects the brain. Existing therapies for HAT have poor safety profiles, difficult treatment regimens, limited effectiveness, and a high cost of goods. Through an integrated drug discovery project, we have discovered and optimized a novel class of boron-containing small molecules, benzoxaboroles, to deliver SCYX-7158, an orally active preclinical drug candidate. SCYX-7158 cured mice infected with T. brucei, both in the blood and in the brain. Extensive pharmacokinetic characterization of SCYX-7158 in rodents and non-human primates supports the potential of this drug candidate for progression to IND-enabling studies in advance of clinical trials for stage 2 HAT

The synthesis of randomly alloyed palladium-silver nanoparticles for the catalytic treatment of aqueous nitrite

Nitrate (NO₃-), and its daughter compound nitrite (NO₂-), are two of the most prevalent contaminants in drinking water. Catalytic degradation of NO₃- and NO₂- provides a treatment method with a small environmental footprint, though it is currently hindered by the need for a catalytic system that pairs reduced costs with enhanced activity and longevity. Monodisperse, randomly-alloyed palladium–silver nanoparticles (Pd [subscript X] Ag [subscript 100-X] NPs) with tunable compositions (X = 50–95) were studied for use as catalysts in aqueous NO₂- reduction. The synthesized Pd [subscript X] Ag [subscript 100-X] NPs were supported on amorphous silica (SiO₂) and studied for use as aqueous NO₂- reduction catalysts in batch reactors with H₂ gas as the electron donor. Nitrite reduction followed pseudo-first-order reaction kinetics for ≥80% conversion, and displayed a high selectivity (>98%) for nitrogen gas (N₂) as the end product. Nearly all compositions displayed increased activity over pure PdNPs supported on amorphous SiO₂. Catalyst longevity was assessed for the most active catalyst. Throughout recycling, the catalytic activity decreased, although complementary analysis indicated no major physical changes of the catalyst. Overall, this work demonstrates that incorporating inexpensive, semi-noble metals into bimetallic alloys is a potential avenue for increasing catalytic activity while decreasing catalyst cost for NO₂- reductionCivil, Architectural, and Environmental Engineerin

Ewing Sarcoma of the 9th Rib Subsequent to Pediatric Leukemia: A Case Series.

Ewing sarcoma is an aggressive malignancy of bone and soft tissue that accounts for ∼2% of cases of childhood cancer. It has been rarely reported as a secondary neoplasm. Data from the Childhood Cancer Survivor Study has evaluated secondary sarcomas in 5-year survivors of childhood cancer. We report 2 pediatric patients in northeast Pennsylvania, who developed secondary Ewing sarcoma of the 9th rib within 5 years of primary childhood leukemia diagnoses

High-throughput small molecule screen identifies inhibitors of aberrant chromatin accessibility

Mutations in chromatin-modifying proteins and transcription factors are commonly associated with a wide variety of cancers. Through gain- or loss-of-function, these mutations may result in characteristic alterations of accessible chromatin, indicative of shifts in the landscape of regulatory elements genome-wide. The identification of compounds that reverse a specific chromatin signature could lead to chemical probes or potential therapies. To explore whether chromatin accessibility could serve as a platform for small molecule screening, we adapted formaldehyde-assisted isolation of regulatory elements (FAIRE), a chemical method to enrich for nucleosome-depleted genomic regions, as a high-throughput, automated assay. After demonstrating the validity and robustness of this approach, we applied this method to screen an epigenetically targeted small molecule library by evaluating regions of aberrant nucleosome depletion mediated by EWSR1-FLI1, the chimeric transcription factor critical for the bone and soft tissue tumor Ewing sarcoma. As a class, histone deacetylase inhibitors were greatly overrepresented among active compounds. These compounds resulted in diminished accessibility at targeted sites by disrupting transcription of EWSR1-FLI1. Capitalizing on precise differences in chromatin accessibility for drug discovery efforts offers significant advantages because it does not depend on the a priori selection of a single molecular target and may detect novel biologically relevant pathways

High-throughput small molecule screen identifies inhibitors of aberrant chromatin accessibility.

Mutations in chromatin-modifying proteins and transcription factors are commonly associated with a wide variety of cancers. Through gain- or loss-of-function, these mutations may result in characteristic alterations of accessible chromatin, indicative of shifts in the landscape of regulatory elements genome-wide. The identification of compounds that reverse a specific chromatin signature could lead to chemical probes or potential therapies. To explore whether chromatin accessibility could serve as a platform for small molecule screening, we adapted formaldehyde-assisted isolation of regulatory elements (FAIRE), a chemical method to enrich for nucleosome-depleted genomic regions, as a high-throughput, automated assay. After demonstrating the validity and robustness of this approach, we applied this method to screen an epigenetically targeted small molecule library by evaluating regions of aberrant nucleosome depletion mediated by EWSR1-FLI1, the chimeric transcription factor critical for the bone and soft tissue tumor Ewing sarcoma. As a class, histone deacetylase inhibitors were greatly overrepresented among active compounds. These compounds resulted in diminished accessibility at targeted sites by disrupting transcription of EWSR1-FLI1. Capitalizing on precise differences in chromatin accessibility for drug discovery efforts offers significant advantages because it does not depend on the a priori selection of a single molecular target and may detect novel biologically relevant pathways