Switch type I to type II TRK inhibitors for combating clinical resistance induced by xDFG mutation for cancer therapy

by Selleckchem | Aug 16 2023

TRK xDFG mutation-induced acquired resistance of 1st generation inhibitors larotrectinib and entrectinib remains an unmet clinical need. Here we report a series of 6-(pyrrolidin-1-yl)imidazo[1,2-b]pyridazine-based derivatives as selective type II TRK inhibitors by hybridization. A representative compound 12d potently inhibited TRKA/B/C and TRKAG667C with IC50 values of 3.3, 6.4, 4.3 and 9.4 nM, respectively. 12d potently suppressed proliferation of a panel of Ba/F3 cells stably transformed with wild type, xDFG as well as solvent-front (SF) mutant TRK fusion proteins. Compared with larotrectinib and selitrectinib, 12d displayed superior inhibitory activity towards Ba/F3 cells harboring CD74-TRKAG667C and ETV6-TRKCG696C with IC50 values of 2.6 and 6.1 nM, respectively. Moreover, 12d also exhibited potent antiproliferation activity against Ba/F3-ETV6-TRKCG623R and Ba/F3-ETV6-TRKCG623E mutants with IC50 values of 31.0 and 28.2 nM, respectively. This work provided a new potential type II TRK inhibitor-based lead compound for the treatment of TRK driven cancers.

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Thank you for sharing this information. It seems that you're referring to a scientific report discussing the development of a series of compounds as selective type II TRK inhibitors for the treatment of cancers driven by TRK mutations.

The TRK (tropomyosin receptor kinase) proteins, including TRKA, TRKB, and TRKC, play a role in various cellular processes and can become oncogenic when fused with other proteins. Larotrectinib and entrectinib are first-generation inhibitors targeting TRK fusion proteins, but their effectiveness can be limited by acquired resistance caused by mutations, particularly the xDFG mutation.

The report describes the development of a series of 6-(pyrrolidin-1-yl)imidazo[1,2-b]pyridazine-based compounds as selective type II TRK inhibitors. A representative compound, 12d, exhibited potent inhibitory activity against TRKA/B/C and TRKAG667C, with IC50 values (concentration required to inhibit 50% of the target activity) ranging from 3.3 to 9.4 nM.

Compound 12d was also effective in suppressing the proliferation of Ba/F3 cells (a commonly used cell line in research) that were transformed with various TRK fusion proteins, including wild type, xDFG, and solvent-front (SF) mutants. Importantly, 12d demonstrated superior inhibitory activity compared to larotrectinib and selitrectinib in Ba/F3 cells harboring CD74-TRKAG667C and ETV6-TRKCG696C mutations, with IC50 values of 2.6 and 6.1 nM, respectively.

Furthermore, 12d exhibited potent antiproliferative activity against Ba/F3 cells with ETV6-TRKCG623R and Ba/F3 cells with ETV6-TRKCG623E mutations, with IC50 values of 31.0 and 28.2 nM, respectively.

Overall, this research presents compound 12d as a promising lead compound for the development of type II TRK inhibitors for the treatment of TRK-driven cancers. The findings suggest that this compound has potent inhibitory activity against a range of TRK fusion proteins, including those associated with acquired resistance to first-generation inhibitors. Further studies and clinical trials will be necessary to assess the potential of these compounds in the treatment of TRK-driven cancers in humans.