AI Article Synopsis
- Tropomyosin receptor kinase (TRK) is a key target for treating cancers caused by NTRK fusions, though resistance mutations can develop from current drugs like larotrectinib and entrectinib.
- A new potent and selective type II TRK inhibitor, 40l, was created using structure-based design and demonstrated significant effectiveness in suppressing cancer cell growth and inducing apoptosis compared to existing therapies.
- The compound 40l shows good selectivity among 41 kinases and maintains stability in plasma, making it a promising candidate for further optimization to address resistance mutations.
Article Abstract
Tropomyosin receptor kinase (TRK) is a promising target for treating NTRK fusion cancers. The solvent front and xDFG mutations induced by larotrectinib and entrectinib result in acquired resistance in advanced-stage patients. In this study, we report a highly potent and selective type II TRK inhibitor, 40l, developed using a structure-based design strategy. Compound 40l significantly suppressed Km-12, Ba/F3-TRKA, and Ba/F3-TRKA cell proliferation. In biochemical and cellular assays, 40l showed better inhibitory activity against TRKA than that by the positive control, selitrectinib. Additionally, it induced apoptosis of Ba/F3-TRKA and Ba/F3-TRKA cells in a dose-dependent manner. Furthermore, 40l showed good selectivity for a panel of 41 kinases. In vitro assays indicated that 40l possessed outstanding plasma stability and moderate liver microsomal stability. Based on the above results, compound 40l could be further optimized to overcome the solvent front and xDFG TRK mutations.
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| http://dx.doi.org/10.1016/j.ejmech.2023.115953 | DOI Listing |
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