Design and synthesis of novel orally selective and type II pan-TRK inhibitors to overcome mutations by property-driven optimization
- Eur J Med Chem. 2021 Nov 15:224:113673. doi: 10.1016/j.ejmech.2021.113673.
- 1. 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.
- 2. Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, No. 35, Keyan Road, Zhunan Town, Miaoli County, 350401, Taiwan, ROC.
- 3. 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: [email protected].
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 (IC50 = 56.4 nM) against the KM12 human colorectal Cancer cell line. 39 also displayed good AUC and oral bioavailability (F = 27%), excellent in vivo efficacy (TGI = 64%) in a KM12 xenograft model, and broad-spectrum anti-TRK mutant potency (IC50 = 3.74-151.4 nM), especially in the double-mutant TrkA enzymatic assays. 39 is therefore proposed for further development as a next-generation, selective, and orally-administered type II Trk Inhibitor.