Identification and Optimization of Small Molecule Pyrazolopyrimidine TLR7 Agonists for Applications in Immuno-oncology.

Small molecule toll-like receptor (TLR) 7 agonists have gathered considerable interest as promising therapeutic agents for applications in cancer immunotherapy. Herein, we describe the development and optimization of a series of novel TLR7 agonists through systematic structure-activity relationship studies focusing on modification of the phenylpiperidine side chain. Additional refinement of ADME properties culminated in the discovery of compound , which displayed nanomolar reporter assay activity and favorable drug-like properties.

Discovery of Novel TLR7 Agonists as Systemic Agent for Combination With aPD1 for Use in Immuno-oncology.

We have designed and developed novel and selective TLR7 agonists that exhibited potent receptor activity in a cell-based reporter assay. , these agonists significantly induced secretion of cytokines IL-6, IL-1β, IL-10, TNFa, IFNa, and IP-10 in human and mouse whole blood. Pharmacokinetic and pharmacodynamic studies in mice showed a significant secretion of IFNα and TNFα cytokines.

Ni/Photoredox-Catalyzed C(sp)-C(sp) Cross-Coupling of Alkyl Pinacolboronates and (Hetero)Aryl Bromides.

Utilizing quinoline as a mild, catalytic additive, broadly applicable conditions for the Ni/photoredox-catalyzed C(sp)-C(sp) cross-coupling of (hetero)aryl bromides and alkyl pinacolboronate esters were developed, which can be applied to both batch and flow reactions. In addition to primary benzylic nucleophiles, both stabilized and nonstabilized secondary alkyl boronic esters are effective coupling partners. Density functional theory calculations suggest that alkyl radical generation occurs from an alkyl-B(pin)-quinoline complex, which may proceed via an energy transfer process.

Digital Interventions to Save Lives From the Opioid Crisis Prior and During the SARS COVID-19 Pandemic: A Scoping Review of Australian and Canadian Experiences.

Background: The potential for digital initiatives for opioid harm reduction is boundless. Synthesized evidence on current interventions and their efficacy are emerging. This scoping review is an effort to aggregate Canadian and Australian digital health initiatives used to prevent opioid-related deaths and minimize harm, prior to and particularly during the pandemic of SARs-COVID-19, when the crisis escalated.

Long-Acting Tumor-Activated Prodrug of a TGFβR Inhibitor.

Inhibition of TGFβ signaling in concert with a checkpoint blockade has been shown to provide improved and durable antitumor immune response in mouse models. However, on-target adverse cardiovascular effects have limited the clinical use of TGFβ receptor (TGFβR) inhibitors in cancer therapy. To restrict the activity of TGFβR inhibitors to tumor tissues and thereby widen the therapeutic index, a series of tumor-activated prodrugs of a selective small molecule TGFβR1 inhibitor were prepared by appending to a serine protease substrate and a half-life extension fatty acid carbon chain.