The Bcr-Abl small molecule inhibitor Imatinib has achieved great success in clinical treatment of diseases such as chronic myeloid leukemia (CML). However, clinical resistance induced by Bcr-Abl mutation has become an important issue in oncology today. The second-generation drugs Nilotinib and Dasatinib can only overcome the resistance caused by some gene mutations, but are not effective for Bcr-AblT315I which has the highest incidence of resistance mutations. In December 2012, ponatinib, which overcomes the resistance of Bcr-AblT315I, was just approved by the US FDA for marketing, but its effect on P-Loop mutations such as Bcr-Abl E255K / V was not good. After nearly 4 years of technical research, the team led by Dr. Ding Ke from Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences successfully designed and synthesized two small molecule inhibitors of aryl alkyne and triazole benzamide. The compound can effectively overcome the drug resistance problem induced by Bcr-AblT315I mutation in various kinases, cells and animal models. Among them, the compound GZD824 can inhibit the kinase activity of Bcr-AblWT and Bcr-AblT315I and other drug-resistant mutants with IC50 value of pM (0.34 and 0.68 nM, respectively), and is effective for P-loop region mutations (E255K / V). The compound showed excellent antitumor activity in a variety of cell and animal models (IC50 for C562 tumor cells such as K562, Ku812 is 0.2 ~ 10 nM; IC50 for Ba / F3 cells carrying the Bcr-AblT315I mutant is approximately 7 nM ; Completely inhibit tumor growth at an oral dose of 1.0-20.0 mg / kg / day) and good safety indicators and excellent pharmacokinetic properties (rat oral bioavailability is about 48.7%; half-life in vivo T1 / 2 about 8-10 hours). At present, GZD824 has been identified as a drug candidate and is undergoing a standardized preclinical evaluation. Based on this project, the research team also won the gold prize in the "Fourth Youth Entrepreneurship Competition of the Chinese Academy of Sciences" in 2011. The research was funded by the National New Drug Creation Major Project, Guangdong New Drug Creation Major Project, Guangzhou Major Project, and the Chinese Academy of Sciences Cross Team Project. Part of the results have been published in the Journal of Medicinal Chemistry J. Med. Chem. [J. Med. Chem. 2013, 56 (3), 879-894; J. Med. Chem. 2012, 55 (22), 10033-10046]. Loaf Pan,Cake Pan,Baking Tray,Baking Sheet Guangdong Qunfa Ceramics Co., Ltd , https://www.qunfaceramics.com
October 06, 2020