2. Academic Validation
  3. Design and synthesis of novel orally selective and type II pan-TRK inhibitors to overcome mutations by property-driven optimization

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.
Mu-Chun Li 1,  Wen-Hsing Lin 2,  Pei-Chen Wang 2,  Yu-Chieh Su 2,  Pei-Yi Chen 2,  Chu-Min Fan 2,  Ching-Ping Chen 2,  Chen-Lung Huang 2,  Chun-Hsien Chiu 2,  Ling Chang 2,  Chiung-Tong Chen 2,  Teng-Kuang Yeh 2,  Hsing-Pang Hsieh 3
Affiliations

Affiliations

  • 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: hphshieh@nhri.edu.tw.
PMID: 34303872 DOI: 10.1016/j.ejmech.2021.113673
Abstract

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.

Keywords

Fusion; Kinase inhibitor; Mutation; Property-driven optimization; Tropomyosin receptor kinase (TRK).

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