479422-74-7Relevant academic research and scientific papers
Discovery of substituted indole derivatives as allosteric inhibitors of m6A-RNA methyltransferase, METTL3-14 complex
Jin, Mi Sun,Kim, Subin,Kim, Yong-Chul,Lee, Je-Heon
, (2022/01/20)
m6A RNA methyltransferase (METTL3-14) catalyzes the methylation of adenosine in mRNA and plays important roles in mRNA functions, and it has been implicated in the progression of multiple cancers, including acute myeloid leukemia (AML). In this study, we describe the discovery of the first allosteric inhibitor of the METTL3-14 complex based on structure–activity relationship (SAR) and optimization studies of the hit compound, 4-[2-[5-chloro-1-(diphenylmethyl)-2-methyl-1H-indol-3-yl]-ethoxy]benzoic acid (CDIBA). Compound 43n was optimized throughout the modifications of 4 different regions of the structure, and it displayed potent enzyme inhibitory activity of the METTL3-14 complex (IC50?=?2.81 μM) and an antiproliferative effect in the AML cell lines by suppressing the m6A level of mRNA. The inhibition mechanism and binding mode of 43n were based on the interaction of the reversible and noncompetitive inhibitory profile at the allosteric site along with selectivity for the METTL3-14 complex relative to each subunit enzyme or truncated complex enzyme.
Inhibition of cytosolic phospholipase A2α: Hit to lead optimization
McKew, John C.,Foley, Megan A.,Thakker, Paresh,Behnke, Mark L.,Lovering, Frank E.,Sum, Fuk-Wah,Tam, Steve,Wu, Kun,Shen, Marina W. H.,Zhang, Wen,Gonzalez, Mario,Liu, Shanghao,Mahadevan, Anu,Sard, Howard,Khor, Soo Peang,Clark, James D.
, p. 135 - 158 (2007/10/03)
Compound 1 was previously reported to be a potent inhibitor of cPLA 2α in both artificial monomeric substrate and cell-based assays. However, 1 was inactive in whole blood assays previously used to characterize cyclooxygenase and lipoxygenase inhibitors. The IC50 of 1 increased dramatically with cell number or lipid/detergent concentration. In an attempt to insert an electrophilic ketone between the indole and benzole acid moieties, we discovered that increasing the distance between the two moieties gave a compound with activity in the GLU (7-hydroxycoumarinyl-γ- linolenate) micelle assay, which contains lipid and detergent. Extensive structure-activity relationship work around this lead identified a potent pharmacophore for cPLA2α inhibition. The IC50s between the GLU micelle and rat whole blood assays correlated highly. No correlation was found for other parameters, including lipophilicity or acidity of the required acid functionality. Compounds 25, 39, and 94 emerged as potent, selective inhibitors of cPLA2α and represent well-validated starting points for further optimization.
