The novel BET inhibitor UM-002 reduces glioblastoma cell proliferation and invasion

Bromodomain and extraterminal domain (BET) proteins have emerged as therapeutic targets in multiple cancers, including the most common primary adult brain tumor glioblastoma (GBM). Although several BET inhibitors have entered clinical trials, few are brain penetrant. We have generated UM-002, a novel brain penetrant BET inhibitor that reduces GBM cell proliferation in vitro and in a human cerebral brain organoid model. Since UM-002 is more potent than other BET inhibitors, it could potentially be developed for GBM treatment. Furthermore, UM-002 treatment reduces the expression of cell-cycle related genes in vivo and reduces the expression of invasion related genes within the non-proliferative cells present in tumors as measured by single cell RNA-sequencing. These studies suggest that BET inhibition alters the transcriptional landscape of GBM tumors, which has implications for designing combination therapies. Importantly, they also provide an integrated dataset that combines in vitro and ex vivo studies with in vivo single-cell RNA-sequencing to characterize a novel BET inhibitor in GBM

Catalytic reductions of nitroaromatic compounds over heterogeneous catalysts with rhenium sub-nanostructures

Abstract Nitroaromatic compounds (NACs) are key contaminants of anthropogenic origin and pose a severe threat to human and animal lives. Although the catalytic activities of Re nanostructures (NSs) are significantly higher than those of other heterogeneous catalysts containing NSs, few studies have been reported on the application of Re-based nanocatalysts for NAC hydrogenation. Accordingly, herein, catalytic reductions of nitrobenzene (NB), 4-nitrophenol (4-NP), 2-nitroaniline (2-NA), 4-nitroaniline (4-NA), and 2,4,6-trinitrophenol (2,4,6-TNP) over new Re-based heterogeneous catalysts were proposed. The catalytic materials were designed to enable effective syntheses and stabilisation of particularly small Re structures over them. Accordingly, catalytic hydrogenations of NACs under mild conditions were significantly enhanced by Re sub-nanostructures (Re-sub-NSs). The highest pseudo-first-order rate constants for NB, 4-NP, 2-NA, 4-NA, and 2,4,6-TNP reductions over the catalyst acquired by stabilising Re using bis(3-aminopropyl)amine (BAPA), which led to Re-sub-NSs with Re concentrations of 16.7 wt%, were 0.210, 0.130, 0.100, 0.180, and 0.090 min−1, respectively

Drug and disease signature integration identifies synergistic combinations in glioblastoma

Inherent or acquired resistance to treatment of glioblastoma (GBM) is nearly universal. Here, the authors introduce a platform to identify synergistic drug combinations for patient-specific treatment of GBM based on gene expression signatures and small molecule perturbation-response profiles

CARM1 Is Essential for Myeloid Leukemogenesis but Dispensable for Normal Hematopoiesis

Chromatin-modifying enzymes, and specifically the protein arginine methyltransferases (PRMTs), have emerged as important targets in cancer. Here, we investigated the role of CARM1 in normal and malignant hematopoiesis. Using conditional knockout mice, we show that loss of CARM1 has little effect on normal hematopoiesis. Strikingly, knockout of Carm1 abrogates both the initiation and maintenance of acute myeloid leukemia (AML) driven by oncogenic transcription factors. We show that CARM1 knockdown impairs cell-cycle progression, promotes myeloid differentiation, and ultimately induces apoptosis. Finally, we utilize a selective, small-molecule inhibitor of CARM1 to validate the efficacy of CARM1 inhibition in leukemia cells in vitro and in vivo. Collectively, this work suggests that targeting CARM1 may be an effective therapeutic strategy for AML. [Display omitted] •Conditional knockout of Carm1 has little effect on normal hematopoiesis•Loss of Carm1 abrogates the initiation and maintenance of AML in mouse models•CARM1 knockdown impairs cell-cycle progression and induces apoptosis in AML cells•A potent and selective CARM1 inhibitor impairs AML cell proliferation Greenblatt et al. show that loss of the protein arginine methyltransfersase CARM1 minimally impacts normal hematopoiesis but strongly impairs leukemogenesis by regulating cell-cycle progression, myeloid differentiation, and apoptosis. Targeting CARM1 reduces AML growth in primary patient samples and mouse models