Discovery of Novel, Potent and Orally Bioavailable SMARCA2 PROTACs with Synergistic Anti-tumor Activity in Combination with KRAS G12C Inhibitors. | LitMetric
Cancer genomic studies have identified frequent mutations in subunits of the SWI/SNF chromatin remodeling complex including in non-small cell lung cancer with a frequency of up to 33% in advanced stage disease, making it the most frequently mutated complex in lung cancer. We and others have identified to be synthetic lethal to indicating SMARCA2 is a high value therapeutic target. Here, we disclose the discovery and characterization of potent, selective and orally bioavailable Cereblon-based SMARCA2 PROTACs. Biochemically, YDR1 and YD54 are potent SMARCA2 degraders with an average DC of 7.7nM and 3.5nM respectively in mutant lung cancer cells. Phenotypically, both YDR1 and YD54 selectively inhibited growth of mutant cancer cells. Further, we showed anti-tumor growth inhibitory activity of YDR1 and YD54 in mutant xenograft models of lung cancer. Finally, we show that YDR1 and YD54 synergize with the KRAS G12C inhibitor sotorasib to inhibit growth of and co-mutant lung cancer cells. These findings provide additional evidence for the utility of single agent or combination regimens containing SMARCA2 PROTACs as synthetic lethal therapeutics against mutant cancers.
Non-small cell lung cancer (NSCLC) is the most pervasive sort of lung cancer with deadly outcome. According to recent studies, a number of neoplastic disorders and ferroptosis are intimately connected. This study aims to identify the role of key ferroptosis-related gene (protein kinase AMP-activated catalytic subunit alpha 2, PRKAA2) and explore new directions for the diagnosis and treatment of NSCLC.
Background: To clearly reveal the correlations between tumor characteristics, age at diagnosis, and epidermal growth factor receptor (EGFR) mutation rates in patients with pulmonary ground-glass opacities (GGOs).
Methods: We retrospectively reviewed 1473 patients with GGOs between January 2015 and May 2020 from two cancer centers. The tumor characteristics and EGFR mutation rates were compared between different age groups.
Department of Hematology, The Affiliated Hospital of Qingdao University, Qingdao University, No. 16 Jiangsu Road, Qingdao, 266000, Shandong Province, China.
A poorer prognosis is thought to be associated with "double expressor lymphomas," which are a subtype of diffuse large B cell lymphomas (DLBCL) that co-express MYC and BCL2. While the role of ubiquitin-specific peptidase 37 (USP37) in lung cancer, where it mediates the deubiquitination and stabilization of c-myc, has been well-documented, its involvement in DLBCL remains unexplored. The use of RT-PCR, immunohistochemistry, or WB test allowed for the detection of elevated USP37 in DLBCL tissues and cells.
Background: Small cell lung cancer (SCLC) is a highly fatal malignancy, the complex tumor microenvironment (TME) is a critical factor affecting SCLC progression. Cancer-associated fibroblasts (CAFs) are crucial components of TME, yet their role in SCLC and the underlying mechanisms during their interaction with SCLC cells remain to be determined.
Methods: Microenvironmental cell components were estimated using transcriptome data from SCLC tissue available in public databases, analyzed with bioinformatic algorithms.
Background: Increased ribosome biogenesis is required for tumor growth. In this study, we investigated the function and underlying molecular mechanism of ribosome biogenesis factor (RBIS) in the progression of non-small cell lung cancer (NSCLC).
Methods: In our study, we conducted a comprehensive analysis to identify key genes implicated in ribosome biogenesis by leveraging a Gene Set Enrichment Analysis (GSEA) dataset.
