713530-47-3Relevant articles and documents
Harnessing the E3 Ligase KEAP1 for Targeted Protein Degradation
Chen, He,Chen, Xian,Jin, Jian,Kumar, Prashasti,Li, Dongxu,Meng, Fanye,Park, Kwang-Su,Shen, Yudao,Teichman, Emily,Velez, Julia,Wang, Gang Greg,Wang, Li,Wei, Jieli,Xie, Ling,Yim, Hyerin,Kaniskan, H. ümit
supporting information, p. 15073 - 15083 (2021/10/01)
Proteolysis targeting chimeras (PROTACs) represent a new class of promising therapeutic modalities. PROTACs hijack E3 ligases and the ubiquitin-proteasome system (UPS), leading to selective degradation of the target proteins. However, only a very limited number of E3 ligases have been leveraged to generate effective PROTACs. Herein, we report that the KEAP1 E3 ligase can be harnessed for targeted protein degradation utilizing a highly selective, noncovalent small-molecule KEAP1 binder. We generated a proof-of-concept PROTAC, MS83, by linking the KEAP1 ligand to a BRD4/3/2 binder. MS83 effectively reduces protein levels of BRD4 and BRD3, but not BRD2, in cells in a concentration-, time-, KEAP1- and UPS-dependent manner. Interestingly, MS83 degrades BRD4/3 more durably than the CRBN-recruiting PROTAC dBET1 in MDA-MB-468 cells and selectively degrades BRD4 short isoform over long isoform in MDA-MB-231 cells. It also displays improved antiproliferative activity than dBET1. Overall, our study expands the limited toolbox for targeted protein degradation.
SYK INHIBITORS
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Paragraph 1295, (2016/10/07)
The present disclosure a Syk compound inhibitors, including state cancer and inflammation and various disease States thereof in the treatment of relates to the use of. In one aspect a particular embodiment, . given by formula I which is marked as a chemical structure of compound. In formula said, X 1, X 2, X 3, R 2, R 3, R 4, R 5, and Y has described herein is. The present disclosure of a formula I compounds or a pharmaceutically acceptable salt of pharmaceutical compositions including, mediated by Syk and to treat conditions a employing these compounds and compositions further provides a method. (by machine translation)
Novel dual-targeting benzimidazole urea inhibitors of DNA gyrase and topoisomerase IV possessing potent antibacterial activity: Intelligent design and evolution through the judicious use of structure-guided design and stucture-activity relationships
Charifson, Paul S.,Grillot, Anne-Laure,Grossman, Trudy H.,Parsons, Jonathan D.,Badia, Michael,Bellon, Steve,Deininger, David D.,Drumm, Joseph E.,Gross, Christian H.,LeTiran, Arnaud,Liao, Yusheng,Mani, Nagraj,Nicolau, David P.,Perola, Emanuele,Ronkin, Steven,Shannon, Dean,Swenson, Lora L.,Tang, Qing,Tessier, Pamela R.,Tian, Ski-Kai,Trudeau, Martin,Wang, Tiansheng,Wei, Yunyi,Zhang, Hong,Stamos, Dean
experimental part, p. 5243 - 5263 (2009/07/01)
The discovery of new antibacterial agents with novel mechanisms of action is necessary to overcome the problem of bacterial resistance that affects all currently used classes of antibiotics. Bacterial DNA gyrase and topoisomerase IV are well-characterized clinically validated targets of the fluoroquinolone antibiotics which exert their antibacterial activity through inhibition of the catalytic subunits. Inhibition of these targets through interaction with their ATP sites has been less clinically successful. The discovery and characterization of a new class of low molecular weight, synthetic inhibitors of gyrase and topoisomerase IV that bind to the ATP sites are presented. The benzimidazole ureas are dual targeting inhibitors of both enzymes and possess potent antibacterial activity against a wide spectrum of relevant pathogens responsible for hospital- and community-acquired infections. The discovery and optimization of this novel class of antibacterials by the use of structure-guided design, modeling, and structure-activity relationships are described. Data are presented for enzyme inhibition, antibacterial activity, and in vivo efficacy by oral and intravenous administration in two rodent infection models.
