In 2019,Journal of Medicinal Chemistry included an article by Wu, Tsung-Sheng; Lin, Wen-Hsing; Tsai, Hui-Jen; Hsueh, Ching-Cheng; Hsu, Tsu; Wang, Pei-Chen; Lin, Hui-You; Peng, Yi-Hui; Lu, Cheng-Tai; Lee, Lung-Chun; Tu, Chih-Hsiang; Kung, Fang-Chun; Shiao, Hui-Yi; Yeh, Teng-Kuang; Song, Jen-Shin; Chang, Jia-Yu; Su, Yu-Chieh; Chen, Li-Tzong; Chen, Chiung-Tong; Jiaang, Weir-Torn; Wu, Su-Ying. Synthetic Route of C4H2Cl2N2. The article was titled 《Discovery of Conformational Control Inhibitors Switching off the Activated c-KIT and Targeting a Broad Range of Clinically Relevant c-KIT Mutants》. The information in the text is summarized as follows:
Drug resistance due to acquired mutations that constitutively activate c-KIT is a significant challenge in the treatment of patients with gastrointestinal stromal tumors (GISTs). Herein, we identified 1-(5-ethyl-isoxazol-3-yl)-3-(4-{2-[6-(4-ethylpiperazin-1-yl)pyrimidin-4-ylamino]-thiazol-5-yl}phenyl)urea (10a) as a potent inhibitor against unactivated and activated c-KIT. The binding of 10a induced rearrangements of the DFG motif, αC-helix, juxtamembrane domain, and the activation loop to switch the activated c-KIT back to its structurally inactive state. To the best of our knowledge, it is the first structural evidence demonstrating how a compound can inhibit the activated c-KIT by switching back to its inactive state through a sequence of conformational changes. Moreover, 10a can effectively inhibit various c-KIT mutants and the proliferation of several GIST cell lines. The distinct binding features and superior inhibitory potency of 10a, together with its excellent efficacy in the xenograft model, establish 10a as worthy of further clin. evaluation in the advanced GISTs.4,6-Dichloropyrimidine(cas: 1193-21-1Synthetic Route of C4H2Cl2N2) was used in this study.
4,6-Dichloropyrimidine(cas: 1193-21-1) is a member of organic chlorides. Almost all organochlorine compounds are synthesized. It is widely used as intermediates, solvents and pesticides of chemical synthetic products.Synthetic Route of C4H2Cl2N2
Referemce:
Pyrimidine | C4H4N2 – PubChem,
Pyrimidine – Wikipedia