Bioorganic & medicinal chemistry letters, Jan 21, 2017
Prostaglandin E2 (PGE2) is a lipid mediator of inflammation and its inhibition has become a popul... more Prostaglandin E2 (PGE2) is a lipid mediator of inflammation and its inhibition has become a popular drug target due to its harmful physiological roles. Diarylheptanoids are one class of compounds that have shown successful inhibition of PGE2. This paper reports the synthesis and PGE2 inhibitory activity of a series of analogues of a naturally occurring diarylheptanoid. The most efficacious compounds were examined for dose-dependent PGE2 inhibition. Among several promising compounds, the lead candidate exhibited an IC50 value of 0.56 ng/µL or 1.7 µM with no detectable toxicity at the highest dose of 10 ng/µL.
BackgroundFragile X syndrome (FXS) is the most common inherited form of intellectual disability a... more BackgroundFragile X syndrome (FXS) is the most common inherited form of intellectual disability affecting 1 in 4,000 males and 1 in 6-8,000 females. FXS is caused by a trinucleotide expansion in the 5’UTR of the Fragile X Mental Retardation (FMR1) gene which in full mutation carriers (>200 repeats) leads to hypermethylation and transcriptional silencing of the gene and lack of expression of Fragile X Protein (FXP, formerly known as Fragile X Mental Retardation Protein, FMRP). Phenotypic presentation of FXS is highly variable, and molecular markers explaining or predicting this variability are lacking. Recent studies suggest that trace amounts of FXP can be detected even in fully methylated individuals and may have clinical relevance; however, the lack of available reproducible, sensitive assays to detect FXP in peripheral tissue makes evaluation of peripheral FXP as a source of clinical variability challenging. MethodsWe optimized a Luminex-based assay to detect FXP in dried blot...
Fragile X syndrome (FXS) is the most common inherited form of intellectual disability and is asso... more Fragile X syndrome (FXS) is the most common inherited form of intellectual disability and is associated with increased risk for autism spectrum disorder (ASD), anxiety, ADHD, and epilepsy. While our understanding of FXS pathophysiology has improved, a lack of validated blood-based biomarkers of disease continues to impede bench-to-bedside efforts. To meet this demand, there is a growing effort to discover a reliable biomarker to inform treatment discovery and evaluate treatment target engagement. Such a marker, amyloid-beta precursor protein (APP), has shown potential dysregulation in the absence of fragile X mental retardation protein (FMRP) and may therefore be associated with FXS pathophysiology. While APP is best understood in the context of Alzheimer disease, there is a growing body of evidence suggesting the molecule and its derivatives play a broader role in regulating neuronal hyperexcitability, a well-characterized phenotype in FXS. To evaluate the viability of APP as a peripheral biological marker in FXS, we conducted an exploratory ELISA-based evaluation of plasma APP-related species involving 27 persons with FXS (mean age: 22.0 ± 11.5) and 25 age-and sex-matched persons with neurotypical development (mean age: 21.1 ± 10.7). Peripheral levels of both Aβ(1-40) and Aβ(1-42) were increased, while sAPPα was significantly decreased in persons with FXS as compared to control participants. These results suggest that dysregulated APP processing, with potential preferential β-secretase processing, may be a readily accessible marker of FXS pathophysiology.
Bioorganic & medicinal chemistry letters, Jan 21, 2017
Prostaglandin E2 (PGE2) is a lipid mediator of inflammation and its inhibition has become a popul... more Prostaglandin E2 (PGE2) is a lipid mediator of inflammation and its inhibition has become a popular drug target due to its harmful physiological roles. Diarylheptanoids are one class of compounds that have shown successful inhibition of PGE2. This paper reports the synthesis and PGE2 inhibitory activity of a series of analogues of a naturally occurring diarylheptanoid. The most efficacious compounds were examined for dose-dependent PGE2 inhibition. Among several promising compounds, the lead candidate exhibited an IC50 value of 0.56 ng/µL or 1.7 µM with no detectable toxicity at the highest dose of 10 ng/µL.
BackgroundFragile X syndrome (FXS) is the most common inherited form of intellectual disability a... more BackgroundFragile X syndrome (FXS) is the most common inherited form of intellectual disability affecting 1 in 4,000 males and 1 in 6-8,000 females. FXS is caused by a trinucleotide expansion in the 5’UTR of the Fragile X Mental Retardation (FMR1) gene which in full mutation carriers (>200 repeats) leads to hypermethylation and transcriptional silencing of the gene and lack of expression of Fragile X Protein (FXP, formerly known as Fragile X Mental Retardation Protein, FMRP). Phenotypic presentation of FXS is highly variable, and molecular markers explaining or predicting this variability are lacking. Recent studies suggest that trace amounts of FXP can be detected even in fully methylated individuals and may have clinical relevance; however, the lack of available reproducible, sensitive assays to detect FXP in peripheral tissue makes evaluation of peripheral FXP as a source of clinical variability challenging. MethodsWe optimized a Luminex-based assay to detect FXP in dried blot...
Fragile X syndrome (FXS) is the most common inherited form of intellectual disability and is asso... more Fragile X syndrome (FXS) is the most common inherited form of intellectual disability and is associated with increased risk for autism spectrum disorder (ASD), anxiety, ADHD, and epilepsy. While our understanding of FXS pathophysiology has improved, a lack of validated blood-based biomarkers of disease continues to impede bench-to-bedside efforts. To meet this demand, there is a growing effort to discover a reliable biomarker to inform treatment discovery and evaluate treatment target engagement. Such a marker, amyloid-beta precursor protein (APP), has shown potential dysregulation in the absence of fragile X mental retardation protein (FMRP) and may therefore be associated with FXS pathophysiology. While APP is best understood in the context of Alzheimer disease, there is a growing body of evidence suggesting the molecule and its derivatives play a broader role in regulating neuronal hyperexcitability, a well-characterized phenotype in FXS. To evaluate the viability of APP as a peripheral biological marker in FXS, we conducted an exploratory ELISA-based evaluation of plasma APP-related species involving 27 persons with FXS (mean age: 22.0 ± 11.5) and 25 age-and sex-matched persons with neurotypical development (mean age: 21.1 ± 10.7). Peripheral levels of both Aβ(1-40) and Aβ(1-42) were increased, while sAPPα was significantly decreased in persons with FXS as compared to control participants. These results suggest that dysregulated APP processing, with potential preferential β-secretase processing, may be a readily accessible marker of FXS pathophysiology.
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Papers by Richard McLane