文献类型：期刊文献

英文题名：Discovery of Potent, Selective Stem Cell Factor Receptor/Platelet Derived Growth Factor Receptor Alpha (c-KIT/PDGFRα) Dual Inhibitor for the Treatment of Imatinib-Resistant Gastrointestinal Stromal Tumors (GISTs)

作者：Lu, Yanli[1];Mao, Fei[1];Li, Xiaokang[1];Zheng, Xinyu[1];Wang, Manjiong[1];Xu, Cling[1];Zhu, Jin[1];Li, Jian[1]

机构：[1]East China Univ Sci & Technol, Sch Pharm, Shanghai Key Lab New Drug Design, Shanghai 200237, Peoples R China

年份：2017

卷号：60

期号：12

起止页码：5099

外文期刊名：JOURNAL OF MEDICINAL CHEMISTRY

收录：;WOS:【SCI-EXPANDED(收录号:WOS:000404202200023)】；

基金：Financial support for this research was provided by the National Natural Science Foundation of China (grants 21672064 and 21372001), the "Shu Guang" project supported by the Shanghai Municipal Education Commission and the Shanghai Education Development Foundation (grant 14SG28), and the Fundamental Research Funds for the Central Universities. We sincerely thank the group of Professor Jonathan A. Fletcher, Brigham and Women's Hospital, Boston, USA, for providing GIST-882 and GIST-48B cells. We gratefully acknowledge Hefei PreceDo Pharmaceuticals Co., Ltd. for the pharmacological evaluation of compound 31.

语种：英文

摘要：Stem cell factor receptor (c-KIT) and platelet derived growth factor receptor alpha (PDGFR alpha) kinasts play an important role in gastrointestinal stromal tumors (GISTs). Here, we have discovered an c-KIT/PDGFR alpha dual inhibitor, compound 31, with single-digit nanomolar potency against c-KIT and PDGFRa. Compared to Imatinib (1), 31 showed better antiproliferative efficacy against various TEL-c-KIT/PD GFR alpha-BaF3 isogenic cells, including three 1-resistant BaF3 cell lines, as well as against GIST-T1 and GIST-882 cell lines. Furthermore, compound 31 showed a good KinomeScan selectivity (468 kinases) (S score (1) = 0.01 at 1 mu M concentration), good metabolic stability in liver microsomes, and no hERG inhibitory activity. It was worth noting that 31 inhibited GIST-T1 tumor growth (TGI = 81.5%) and even the BaF3-TEL-cKIT-T6701 tumor progression (TGI = 41.9%, 1-resistant GISTs) at a dosage of 100 mg/kg/day without exhibiting apparent toxicity.