Eur J Med Chem 2021 Jun 29;224:113673. Epub 2021 Jun 29.
Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, No. 35, Keyan Road, Zhunan Town, Miaoli County, 350401, Taiwan, ROC; Department of Chemistry, National Tsing Hua University, No. 101, Sec. 2, Kuang-Fu Road, Hsinchu, 300044, Taiwan, ROC; Biomedical Translation Research Center, Academia Sinica, No. 99, Ln. 130, Sec. 1, Academia Road, Taipei City, 115202, Taiwan, ROC. Electronic address:
Rare oncogenic NTRK gene fusions result in uncontrolled TRK signaling leading to various adult and pediatric solid tumors. Based on the architecture of our multi-targeted clinical candidate BPR1K871 (10), we designed and synthesized a series of quinazoline compounds as selective and orally bioavailable type II TRK inhibitors. Property-driven and lead optimization strategies informed by structure-activity relationship studies led to the identification of 39, which showed higher (about 15-fold) selectivity for TRKA over AURA and AURB, as well as potent cellular activity (IC = 56. Read More