85 research outputs found
Dysregulation of PRMT5 in chronic lymphocytic leukemia promotes progression with high risk of Richter's transformation
: Richter's Transformation (RT) is a poorly understood and fatal progression of chronic lymphocytic leukemia (CLL) manifesting histologically as diffuse large B-cell lymphoma. Protein arginine methyltransferase 5 (PRMT5) is implicated in lymphomagenesis, but its role in CLL or RT progression is unknown. We demonstrate herein that tumors uniformly overexpress PRMT5 in patients with progression to RT. Furthermore, mice with B-specific overexpression of hPRMT5 develop a B-lymphoid expansion with increased risk of death, and Eµ-PRMT5/TCL1 double transgenic mice develop a highly aggressive disease with transformation that histologically resembles RT; where large-scale transcriptional profiling identifies oncogenic pathways mediating PRMT5-driven disease progression. Lastly, we report the development of a SAM-competitive PRMT5 inhibitor, PRT382, with exclusive selectivity and optimal in vitro and in vivo activity compared to available PRMT5 inhibitors. Taken together, the discovery that PRMT5 drives oncogenic pathways promoting RT provides a compelling rationale for clinical investigation of PRMT5 inhibitors such as PRT382 in aggressive CLL/RT cases
Structure–Activity Relationships and Discovery of a G Protein Biased μ Opioid Receptor Ligand, [(3-Methoxythiophen-2-yl)methyl]({2-[(9<i>R</i>)‑9-(pyridin-2-yl)-6-oxaspiro-[4.5]decan-9-yl]ethyl})amine (TRV130), for the Treatment of Acute Severe Pain
The concept of “ligand bias”
at G protein coupled
receptors has been introduced to describe ligands which preferentially
stimulate one intracellular signaling pathway over another. There
is growing interest in developing biased G protein coupled receptor
ligands to yield safer, better tolerated, and more efficacious drugs.
The classical μ opioid morphine elicited increased efficacy
and duration of analgesic response with reduced side effects in β-arrestin-2
knockout mice compared to wild-type mice, suggesting that G protein
biased μ opioid receptor agonists would be more efficacious
with reduced adverse events. Here we describe our efforts to identify
a potent, selective, and G protein biased μ opioid receptor
agonist, TRV130 ((<i><b>R</b></i>)-<b>30</b>). This novel molecule demonstrated an improved therapeutic index
(analgesia vs adverse effects) in rodent models and characteristics
appropriate for clinical development. It is currently being evaluated
in human clinical trials for the treatment of acute severe pain
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