Discovery of 3-Benzyl-1-(trans-4-((5-cyanopyridin-2-yl)amino)cyclohexyl)-1-arylurea Derivatives as Novel and Selective Cyclin-Dependent Kinase 12 (CDK12) Inhibitors was written by Ito, Masahiro;Tanaka, Toshio;Toita, Akinori;Uchiyama, Noriko;Kokubo, Hironori;Morishita, Nao;Klein, Michael G.;Zou, Hua;Murakami, Morio;Kondo, Mitsuyo;Sameshima, Tomoya;Araki, Shinsuke;Endo, Satoshi;Kawamoto, Tomohiro;Morin, Gregg B.;Aparicio, Samuel A.;Nakanishi, Atsushi;Maezaki, Hironobu;Imaeda, Yasuhiro. And the article was included in Journal of Medicinal Chemistry in 2018.Safety of 6-Fluoronicotinonitrile This article mentions the following:
Cyclin-dependent kinase 12 (CDK12) plays a key role in the coordination of transcription with elongation and mRNA processing. CDK12 mutations found in tumors and CDK12 inhibition sensitize cancer cells to DNA-damaging reagents and DNA-repair inhibitors. This suggests that CDK12 inhibitors are potential therapeutics for cancer that may cause synthetic lethality. Here, we report the discovery of 3-benzyl-1-(trans-4-((5-cyanopyridin-2-yl)amino)cyclohexyl)-1-arylurea derivatives as novel and selective CDK12 inhibitors. Structure-activity relationship studies of a HTS hit, structure-based drug design, and conformation-oriented design using the Cambridge Structural Database afforded the optimized compound 2, which exhibited not only potent CDK12 (and CDK13) inhibitory activity and excellent selectivity but also good physicochem. properties. Furthermore, 2 inhibited the phosphorylation of Ser2 in the C-terminal domain of RNA polymerase II and induced growth inhibition in SK-BR-3 cells. Therefore, 2 represents an excellent chem. probe for functional studies of CDK12 and could be a promising lead compound for drug discovery. In the experiment, the researchers used many compounds, for example, 6-Fluoronicotinonitrile (cas: 3939-12-6Safety of 6-Fluoronicotinonitrile).
6-Fluoronicotinonitrile (cas: 3939-12-6) belongs to pyridine derivatives. The pyridine ring occurs in many important compounds, including agrochemicals, pharmaceuticals, and vitamins. Many analogues of pyridine are known where N is replaced by other heteroatoms . Substitution of one C–H in pyridine with a second N gives rise to the diazine heterocycles (C4H4N2), with the names pyridazine, pyrimidine, and pyrazine.Safety of 6-Fluoronicotinonitrile