Design and synthesis of novel orally selective and type II pan-TRK inhibitors to overcome mutations by property-driven optimization.
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Li MC, Lin WH, Wang PC, Su YC, Chen PY, Fan CM, Chen CP, Huang CL, Chiu CH, Chang L, Chen CT, Yeh TK, Hsieh HP
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. Epub 2021 Jun 29.
- PubMed ID
- 34303872 [ View in PubMed]
- 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 (IC(50) = 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 (IC(50) = 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.