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 = 56.4 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 = 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.
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A phase II trial of larotrectinib in tumors with NTRK fusions or extremes of NTRK mRNA overexpression identified by comprehensive genomic profiling.
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Background: TRK-inhibitors have demonstrated efficacy across several cancers with NTRK fusions. Their activity in cancers with NTRK overexpression remains unclear.
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View Article and Find Full Text PDFERK signaling promotes resistance to TRK kinase inhibition in NTRK fusion-driven glioma mouse models.
Cell Rep
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Human Biology Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA; Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA; Department of Neurosurgery, Clinical Neurosciences Center, University of Utah, Salt Lake City, UT 84112, USA. Electronic address:
Article Synopsis
- - Pediatric high-grade gliomas often have gene fusions with receptor tyrosine kinase genes, such as NTRK, leading to high initial responses to treatment but eventual recurrence due to new mutations.
- - Researchers created mouse models of gliomas driven by NTRK fusions to study how different genetic variations influence tumor characteristics and aggressiveness.
- - While TRK kinase inhibitors improve survival rates in these mice, they do not eliminate the tumors, with recurrence likely due to ERK activation; combining these inhibitors with MEK inhibitors might enhance treatment effectiveness.
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