作者: Andrei, Pietro ; Gionfriddo, Giulia ; Reilly, Nicole Megan ; Linnebacher, Michael ; Arena, Sabrina ; Corti, Giorgio ; Bardelli, Alberto ; Grasso, Gaia ; Lorenzato, Annalisa ; Crisafulli, Giovanni ; Miotto, Martina ; Barault, Ludovic ; Buzo, Kristi ; Mariella, Elisa ; Di Nicolantonio, Federica ; Cancelliere, Carlotta ; Russo, Mariangela ; Vitiello, Pietro Paolo ; Rospo, Giuseppe

Multiple strategies are continuously being explored to expand the drug target repertoire in solid tumors. We devised a novel computational workflow for transcriptome‐wide gene expression outlier analysis that allows the systematic identification of both overexpression and underexpression events in cancer cells. Here, it was applied to expression values obtained through RNA sequencing in 226 colorectal cancer (CRC) cell lines that were also characterized by whole‐exome sequencing and microarray‐based DNA methylation profiling. We found cell models displaying an abnormally high or low expression level for 3533 and 965 genes, respectively. Gene expression abnormalities that have been previously associated with clinically relevant features of CRC cell lines were confirmed. Moreover, by integrating multi‐omics data, we identified both genetic and epigenetic alternations underlying outlier expression values. Importantly, our atlas of CRC gene expression outliers can guide the discovery of novel drug targets and biomarkers. As a proof of concept, we found that CRC cell lines lacking expression of the MTAP gene are sensitive to treatment with a PRMT5‐MTA inhibitor (MRTX1719). Finally, other tumor types may also benefit from this approach.

2024-04-01·European Journal of Medicinal Chemistry

Synthesis and biological evaluation of 1-phenyl-tetrahydro-β-carboline-based first dual PRMT5/EGFR inhibitors as potential anticancer agents

Article

作者: Liu, Xuliang ; Sa, Na ; Jiang, Cheng-Shi ; Zhang, Jin-He ; Zhu, Kong-Kai ; Wang, Kai-Ming ; Xu, Wei ; Zhang, Juan ; Cai, Yong-Si

Protein arginine methyltransferase 5 (PRMT5) and epidermal growth factor receptor (EGFR) are both involved in the regulation of various cancer-related processes, and their dysregulation or overexpression has been observed in many types of tumors. In this study, we designed and synthesized a series of 1-phenyl-tetrahydro-β-carboline (THβC) derivatives as the first class of dual PRMT5/EGFR inhibitors. Among the synthesized compounds, 10p showed the most potent dual PRMT5/EGFR inhibitory activity, with IC₅₀ values of 15.47 ± 1.31 and 19.31 ± 2.14 μM, respectively. Compound 10p also exhibited promising antiproliferative activity against A549, MCF7, HeLa, and MDA-MB-231 cell lines, with IC₅₀ values below 10 μM. Molecular docking studies suggested that 10p could bind to PRMT5 and EGFR through hydrophobic, π-π, and cation-π interactions. Furthermore, 10p displayed favorable pharmacokinetic properties and oral bioavailability (F = 30.6%) in rats, and administrated orally 10p could significantly inhibit the growth of MCF7 orthotopic xenograft tumors. These results indicate that compound 10p is a promising hit compound for the development of novel and effective dual PRMT5/EGFR inhibitors as potential anticancer agents.

100 项与 PRMT5/MTA Inhibitor (Mirati Therapeutics) 相关的药物交易

登录后查看更多信息