Zhang, Lingtian; Moccia, Marialuisa; Briggs, David C.; Bharate, Jaideep B.; Lakkaniga, Naga Rajiv; Knowles, Phillip; Yan, Wei; Tran, Phuc; Kharbanda, Anupreet; Wang, Xiuqi; Leung, Yuet-Kin; Frett, Brendan; Santoro, Massimo; McDonald, Neil Q.; Carlomagno, Francesca; Li, Hong-yu published an article on January 27 ,2022. The article was titled 《Discovery of N-Trisubstituted Pyrimidine Derivatives as Type I RET and RET Gatekeeper Mutant Inhibitors with a Novel Kinase Binding Pose》, and you may find the article in Journal of Medicinal Chemistry.Application of 930-36-9 The information in the text is summarized as follows:
Mutations of the rearranged during transfection (RET) kinase are frequently reported in cancer, which make it as an attractive therapeutic target. Herein, we discovered a series of N-trisubstituted pyrimidine derivatives as potent inhibitors for both wild-type (weight) RET and RETV804M, which is a resistant mutant for several FDA-approved inhibitors. The X-ray structure of a representative inhibitor with RET revealed that the compound binds in a unique pose that bifurcates beneath the P-loop and confirmed the compound as a type I inhibitor. Through the structure-activity relationship (SAR) study, compound 20 (I) was identified as a lead compound, showing potent inhibition of both RET and RETV804M. Addnl., compound 20 displayed potent antiproliferative activity of CCDC6-RET-driven LC-2/ad cells. Anal. of RET phosphorylation indicated that biol. activity was mediated by RET inhibition. Collectively, N-trisubstituted pyrimidine derivatives could serve as scaffolds for the discovery and development of potent inhibitors of type I RET and its gatekeeper mutant for the treatment of RET-driven cancers. The results came from multiple reactions, including the reaction of 1-Methylpyrazole(cas: 930-36-9Application of 930-36-9)
1-Methylpyrazole(cas: 930-36-9) belongs to pyrazoles. Pyrazoles and their related multiring analogs are common elements of a wide variety of bioactive compounds. These ring structures are rare in nature. A consequence of this is that they have previously been thought to be poor moieties to include in potential new drugs. Application of 930-36-9
Referemce:
Pyrazole – Wikipedia,
Pyrazoles – an overview | ScienceDirect Topics