17649-86-4Relevant articles and documents
Design, Synthesis, and Pharmacological Evaluation of Second Generation EZH2 Inhibitors with Long Residence Time
Apte, Shruti,Arora, Shilpi,Audia, James E.,Bradley, William D.,Brenneman, Jehrod,Bruderek, Kamil,Cantone, Nico,Cummings, Richard T.,Gehling, Victor S.,Khanna, Avinash,Levell, Julian R.,Moine, Ludivine,Ramakrishnan, Ashwin,Sims, Robert J.,Stuckey, Jacob I.,Trojer, Patrick,C?té, Alexandre
, p. 1205 - 1212 (2020)
Histone methyltransferase EZH2, which is the catalytic subunit of the PRC2 complex, catalyzes the methylation of histone H3K27 - a transcriptionally repressive post-translational modification (PTM). EZH2 is commonly mutated in hematologic malignancies and frequently overexpressed in solid tumors, where its expression level often correlates with poor prognosis. First generation EZH2 inhibitors are beginning to show clinical benefit, and we believe that a second generation EZH2 inhibitor could further build upon this foundation to fully realize the therapeutic potential of EZH2 inhibition. During our medicinal chemistry campaign, we identified 4-thiomethyl pyridone as a key modification that led to significantly increased potency and prolonged residence time. Leveraging this finding, we optimized a series of EZH2 inhibitors, with enhanced antitumor activity and improved physiochemical properties, which have the potential to expand the clinical use of EZH2 inhibition.
Antitubercular 2-Pyrazolylpyrimidinones: Structure-Activity Relationship and Mode-of-Action Studies
Soares De Melo, Candice,Singh, Vinayak,Myrick, Alissa,Simelane, Sandile B.,Taylor, Dale,Brunschwig, Christel,Lawrence, Nina,Schnappinger, Dirk,Engelhart, Curtis A.,Kumar, Anuradha,Parish, Tanya,Su, Qin,Myers, Timothy G.,Boshoff, Helena I. M.,Barry, Clifton E.,Sirgel, Frederick A.,Van Helden, Paul D.,Buchanan, Kirsteen I.,Bayliss, Tracy,Green, Simon R.,Ray, Peter C.,Wyatt, Paul G.,Basarab, Gregory S.,Eyermann, Charles J.,Chibale, Kelly,Ghorpade, Sandeep R.
supporting information, p. 719 - 740 (2021/02/03)
Phenotypic screening of a Medicines for Malaria Venture compound library against Mycobacterium tuberculosis (Mtb) identified a cluster of pan-active 2-pyrazolylpyrimidinones. The biology triage of these actives using various tool strains of Mtb suggested a novel mechanism of action. The compounds were bactericidal against replicating Mtb and retained potency against clinical isolates of Mtb. Although selected MmpL3 mutant strains of Mtb showed resistance to these compounds, there was no shift in the minimum inhibitory concentration (MIC) against a mmpL3 hypomorph, suggesting mutations in MmpL3 as a possible resistance mechanism for the compounds but not necessarily as the target. RNA transcriptional profiling and the checkerboard board 2D-MIC assay in the presence of varying concentrations of ferrous salt indicated perturbation of the Fe-homeostasis by the compounds. Structure-activity relationship studies identified potent compounds with good physicochemical properties and in vitro microsomal metabolic stability with moderate selectivity over cytotoxicity against mammalian cell lines.
MODULATORS OF METHYL MODIFYING ENZYMES, COMPOSITIONS AND USES THEREOF
-
Paragraph 0082; 0085; 0086, (2019/05/30)
Provided are compounds of Formula (I): and pharmaceutically acceptable salts and compositons thereof, which are useful for treating a variety of conditions associated with methyl modifying enzymes.
