Novel WRN Helicase Inhibitors Selectively Target Microsatellite-Unstable Cancer Cells.

Microsatellite-unstable (MSI) cancers require WRN helicase to resolve replication stress due to expanded DNA (TA)n dinucleotide repeats. WRN is a promising synthetic lethal target for MSI tumors, and WRN inhibitors are in development. In this study, we used CRISPR-Cas9 base editing to map WRN residues critical for MSI cells, validating the helicase domain as the primary drug target.

Antisense Oligonucleotide Remodels the Suppressive Tumor Microenvironment to Enhance Immune Activation in Combination with Anti-PD-L1.

Purpose: Danvatirsen is a therapeutic antisense oligonucleotide (ASO) that selectively targets and has shown clinical activity in two phase I clinical studies. We interrogated the clinical mechanism of action using danvatirsen-treated patient samples and conducted back-translational studies to further elucidate its immunomodulatory mechanism of action.

Experimental Design: Paired biopsies and blood samples from danvatirsen-treated patients were evaluated using immunohistochemistry and gene-expression analysis.

Small molecule AZD4635 inhibitor of AR signaling rescues immune cell function including CD103 dendritic cells enhancing anti-tumor immunity.

Unlabelled: Accumulation of extracellular adenosine within the microenvironment is a strategy exploited by tumors to escape detection by the immune system. Adenosine signaling through the adenosine 2A receptor (AR) on immune cells elicits a range of immunosuppressive effects which promote tumor growth and limit the efficacy of immune checkpoint inhibitors. Preclinical data with AR inhibitors have demonstrated tumor regressions in mouse models by rescuing T cell function; however, the mechanism and role on other immune cells has not been fully elucidated.

Discovery of (2)--[3-[2-[(3-Methoxy-1-methyl-pyrazol-4-yl)amino]pyrimidin-4-yl]-1-indol-7-yl]-2-(4-methylpiperazin-1-yl)propenamide (AZD4205) as a Potent and Selective Janus Kinase 1 Inhibitor.

JAK1, JAK2, JAK3, and TYK2 belong to the JAK (Janus kinase) family. They play critical roles in cytokine signaling. Constitutive activation of JAK/STAT pathways is associated with a wide variety of diseases.

Expression of the cysteine protease legumain in vascular lesions and functional implications in atherogenesis.

Objective: The present study was conducted to characterize the expression of the cysteine protease legumain in murine and human atherosclerotic tissues, and to explore the molecular mechanisms by which legumain may contribute to the pathophysiology of atherosclerosis.

Methods And Results: Using microarray analysis, legumain mRNA expression was found to increase with development of atherosclerosis in the aorta of aging Apolipoprotein E deficient mice while expression remained at low level and unchanged in arteries of age-matched C57BL/6 control mice. In situ hybridization and immunohistochemical analysis determined that legumain was predominantly expressed by macrophages in the atherosclerotic aorta, in lesions at the aortic sinus and in injured carotid arteries of Apolipoprotein E deficient mice as well as in inflamed areas in advanced human coronary atherosclerotic plaques.