10 research outputs found
mRNA knockdown by single strand RNA is improved by chemical modifications
While RNAi has traditionally relied on RNA duplexes, early evaluation of siRNAs demonstrated activity of the guide strand in the absence of the passenger strand. However, these single strands lacked the activity of duplex RNAs. Here, we report the systematic use of chemical modifications to optimize single-strand RNA (ssRNA)-mediated mRNA knockdown. We identify that 2ā²F ribose modifications coupled with 5ā²-end phosphorylation vastly improves ssRNA activity both in vitro and in vivo. The impact of specific chemical modifications on ssRNA activity implies an Ago-mediated mechanism but the hallmark mRNA cleavage sites were not observed which suggests ssRNA may operate through a mechanism beyond conventional Ago2 slicer activity. While currently less potent than duplex siRNAs, with additional chemical optimization and alternative routes of delivery, chemically modified ssRNAs could represent a powerful RNAi platform
Amyloid precursor protein selective gamma-secretase inhibitors for treatment of Alzheimer's disease
Targeting the AAA ATPase p97 as an Approach to Treat Cancer through Disruption of Protein Homeostasis
p97 is a AAA-ATPase with multiple cellular functions, one of which is critical regulation of protein homeostasis pathways. We describe the characterization of CB-5083, a potent, selective, and orally bioavailable inhibitor of p97. Treatment of tumor cells with CB-5083 leads to accumulation of poly-ubiquitinated proteins, retention of endoplasmic reticulum-associated degradation (ERAD) substrates, and generation of irresolvable proteotoxic stress, leading to activation of the apoptotic arm of the unfolded protein response. In xenograft models, CB-5083 causes modulation of key p97-related pathways, induces apoptosis, and has antitumor activity in a broad range of both hematological and solid tumor models. Molecular determinants of CB-5083 activity include expression of genes in the ERAD pathway, providing a potential strategy for patient selection
Discovery of a First-in-Class, Potent, Selective, and Orally Bioavailable Inhibitor of the p97 AAA ATPase (CB-5083)
The AAA-ATPase p97 plays vital roles
in mechanisms of protein homeostasis,
including ubiquitināproteasome system (UPS) mediated protein
degradation, endoplasmic reticulum-associated degradation (ERAD),
and autophagy. Herein we describe our lead optimization efforts focused
on in vitro potency, ADME, and pharmaceutical
properties that led to the discovery of a potent, ATP-competitive,
D2-selective, and orally bioavailable p97 inhibitor <b>71</b>, CB-5083. Treatment of tumor cells with <b>71</b> leads to
significant accumulation of markers associated with inhibition of
UPS and ERAD functions, which induces irresolvable proteotoxic stress
and cell death. In tumor bearing mice, oral administration of <b>71</b> causes rapid accumulation of markers of the unfolded protein
response (UPR) and subsequently induces apoptosis leading to sustained
antitumor activity in in vivo xenograft models of both solid and hematological
tumors. <b>71</b> has been taken into phase 1 clinical trials
in patients with multiple myeloma and solid tumors
Discovery of a First-in-Class, Potent, Selective, and Orally Bioavailable Inhibitor of the p97 AAA ATPase (CB-5083)
The AAA-ATPase p97 plays vital roles
in mechanisms of protein homeostasis,
including ubiquitināproteasome system (UPS) mediated protein
degradation, endoplasmic reticulum-associated degradation (ERAD),
and autophagy. Herein we describe our lead optimization efforts focused
on in vitro potency, ADME, and pharmaceutical
properties that led to the discovery of a potent, ATP-competitive,
D2-selective, and orally bioavailable p97 inhibitor <b>71</b>, CB-5083. Treatment of tumor cells with <b>71</b> leads to
significant accumulation of markers associated with inhibition of
UPS and ERAD functions, which induces irresolvable proteotoxic stress
and cell death. In tumor bearing mice, oral administration of <b>71</b> causes rapid accumulation of markers of the unfolded protein
response (UPR) and subsequently induces apoptosis leading to sustained
antitumor activity in in vivo xenograft models of both solid and hematological
tumors. <b>71</b> has been taken into phase 1 clinical trials
in patients with multiple myeloma and solid tumors