Liu, Xuesong; Wang, Beilei; Chen, Cheng; Qi, Ziping; Zou, Fengming; Wang, Junjie; Hu, Chen; Wang, Aoli; Ge, Juan; Liu, Qingwang; Yu, Kailin; Hu, Zhenquan; Jiang, Zongru; Wang, Wei; Wang, Li; Wang, Wenchao; Ren, Tao; Bai, Mingfeng; Liu, Qingsong; Liu, Jing published the artcile< Discovery of (E)-N1-(3-Fluorophenyl)-N3-(3-(2-(pyridin-2-yl)vinyl)-1H-indazol-6-yl)malonamide (CHMFL-KIT-033) as a Novel c-KIT T670I Mutant Selective Kinase Inhibitor for Gastrointestinal Stromal Tumors (GISTs)>, Reference of 229009-40-9, the main research area is CHMFL KIT033 preparation cKIT T670I kinase inhibitor gastrointestinal tumor.
Gain-of-function mutations of c-KIT kinase play crucial pathol. roles for the gastrointestinal stromal tumors (GISTs). Despite the success of imatinib as the first-line treatment of GISTs, dozens of drug-acquired resistant mutations emerge, and c-KIT T670I is one of the most common mutants among them. Although several kinase inhibitors are capable of overcoming the T670I mutant, none of them can achieve the selectivity over the c-KIT wild-type (wt), which also plays important roles in a variety of physiol. functions such as hematopoiesis. Starting from axitinib, through fragment hybrid type II kinase inhibitor design approach, we have discovered a novel inhibitor 24, which not only exhibits potent activity to c-KIT T670I mutant but also achieves 12-fold selectivity over c-KIT weight Compound 24 displays good antiproliferative effects against c-KIT T670I mutant-driven GIST cell lines (GIST-T1/T670I and GIST-5R) and also exhibits suitable in vivo pharmacokinetic profiles as well as dose-dependent antitumor efficacy. This study provides a proof of concept for developing a c-KIT mutant selective inhibitor that theor. can render a better therapeutic window.
Journal of Medicinal Chemistry published new progress about Antiproliferative agents. 229009-40-9 belongs to class piperazines, and the molecular formula is C11H17BN2O2, Reference of 229009-40-9.
Referemce:
Piperazine – Wikipedia,
Piperazines – an overview | ScienceDirect Topics