Design and synthesis of novel orally selective and type II pan-TRK inhibitors to overcome mutations by
Mu-Chun Li1, Wen-Hsing Lin2, Pei-Chen Wang2
1Institute 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.
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.
Insights
Researchers developed a novel TRK inhibitor, compound 39, demonstrating potent anti-cancer activity against NTRK gene fusion-driven tumors. This orally bioavailable drug candidate shows promising efficacy and selectivity for further development.
Area of Science:
- Medicinal Chemistry
- Oncology
- Drug Discovery
Background:
- NTRK gene fusions drive oncogenesis in various solid tumors, leading to uncontrolled TRK signaling.
- Targeting TRK signaling pathways is a key strategy for treating NTRK-driven cancers.
Purpose of the Study:
- To design and synthesize novel, selective, orally bioavailable type II TRK inhibitors.
- To identify a lead compound for further preclinical development against NTRK-driven tumors.
Main Methods:
- Structure-activity relationship (SAR) studies and lead optimization were employed.
- Synthesis of quinazoline-based compounds.
- In vitro assays for selectivity, cellular activity (IC50), and enzymatic potency.
- In vivo efficacy studies using a KM12 xenograft model.
Main Results:
- Compound 39, a quinazoline derivative, was identified as a potent TRK inhibitor.
- 39 exhibited high selectivity for TRKA over AURKA and AURKB (approx. 15-fold).
- Potent cellular activity (IC50 = 56.4 nM) against KM12 colorectal cancer cells.
- Demonstrated good oral bioavailability (F = 27%) and in vivo efficacy (TGI = 64%).
- Showed broad-spectrum anti-TRK mutant potency, particularly against double-mutant TRKA.
Conclusions:
- Compound 39 is a promising next-generation, selective, orally administered type II TRK inhibitor.
- Further development of 39 is warranted for treating NTRK-driven cancers.
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