Showing papers by "Robert W. Myers published in 2021"
TL;DR: An integrated workflow has been established that enables the synthesis, purification, and subsequent biological testing of compound libraries on a microgram scale as discussed by the authors, which utilizes mass directed preparative HPLC in conjunction with charged aerosol detection (CAD) to generate solutions of investigational compounds at high purity and standardized concentrations.
Abstract: An integrated workflow has been established that enables the synthesis, purification, and subsequent biological testing of compound libraries on a microgram scale This approach utilizes mass directed preparative HPLC in conjunction with charged aerosol detection (CAD) to generate solutions of investigational compounds at high purity and standardized concentrations, facilitating high fidelity biological testing This new workflow successfully delivered libraries of histone deacetylase (HDAC) inhibitors that afforded biological data consistent with that obtained from standard scale parallel medicinal chemistry techniques The advantages of this new approach to library synthesis include greatly reduced material requirements and amenability to high-throughput experimentation
9 citations
TL;DR: In this paper, the discovery of histone deacetylase (HDACs) 1, 2, and 3 inhibitors with ethyl ketone as the zinc-binding group was described.
Abstract: We describe the discovery of histone deacetylase (HDACs) 1, 2, and 3 inhibitors with ethyl ketone as the zinc-binding group. These HDACs 1, 2, and 3 inhibitors have good enzymatic and cellular activity. Their serum shift in cellular potency has been minimized, and selectivity against hERG has been improved. They are also highly selective over HDACs 6 and 8. These inhibitors contain a variety of substituted heterocycles on the imidazole or oxazole scaffold. Compounds 31 and 48 stand out due to their good potency, high selectivity over HDACs 6 and 8, reduced hERG activity, optimized serum shift in cellular potency, and good rat and dog PK profiles.
8 citations
TL;DR: Among 9,048 people infected with SARS-CoV-2 between January-May- 2021 in Maryland, in regression-adjusted analysis, the spike protein mutation E484K was disproportionately prevalent among persons infected after full vaccination against COVID-19 as compared to infected persons who were not fully vaccinated as discussed by the authors.
Abstract: Among 9,048 people infected with SARS-CoV-2 between January-May, 2021 in Maryland, in regression-adjusted analysis, SARS-CoV-2 viruses carrying the spike protein mutation E484K were disproportionately prevalent among persons infected after full vaccination against COVID-19 as compared to infected persons who were not fully vaccinated (aOR 1.96, 95% CI, 1.36 to 2.83).
8 citations
TL;DR: In this paper, a series of histone deacetylase (HDAC) inhibitors lacking a zinc-binding moiety has been developed and described and described in terms of off-target profiles.
Abstract: A novel series of histone deacetylase (HDAC) inhibitors lacking a zinc-binding moiety has been developed and described herein. HDAC isozyme profiling and kinetic studies indicate that these inhibitors display a selectivity preference for HDACs 1, 2, 3, 10, and 11 via a rapid equilibrium mechanism, and crystal structures with HDAC2 confirm that these inhibitors do not interact with the catalytic zinc. The compounds are nonmutagenic and devoid of electrophilic and mutagenic structural elements and exhibit off-target profiles that are promising for further optimization. The efficacy of this new class in biochemical and cell-based assays is comparable to the marketed HDAC inhibitors belinostat and vorinostat. These results demonstrate that the long-standing pharmacophore model of HDAC inhibitors requiring a metal binding motif should be revised and offers a distinct class of HDAC inhibitors.
8 citations
TL;DR: A series of unique macrocyclic HDACs 1, 2, and 3 selective inhibitors were identified with good enzymatic activity and high selectivity over HDAC 6 and 8 as discussed by the authors.
4 citations