Discovery of novel diarylurea derivatives as potent type II TRK inhibitors for combating multiple acquired resistant mutants

Tropomyosin receptor kinases (TRKs), a superfamily of transmembrane Receptor Tyrosine Kinases, have recently attracted extensive attention as promising Cancer therapeutic targets since the FDA approval of Larotrectinib and Entrectinib. However, the emergence of acquired resistance due to secondary mutations in the TRKs domain significantly diminshes the therapeutic efficacy of these drugs, highlighting an urgent unmet clinical need. In this study, we designed a series of novel diarylurea derivatives as potential type II Trk inhibitors, using a molecular hybridization strategy. The representative compound 18d potently inhibited TrkA^{WT/G595R/G667C} with IC₅₀ values of 0.82 nM, 1.82 nM, and 0.12 nM, respectively. It also showed superior antiproliferative activities against both BaF3-LMNA-TRKA^G595R and BaF3-LMNA-TRKA^G667C cell lines (IC₅₀ = 23.76 nM and 0.33 nM, respectively), outperforming Repotrectinib (IC₅₀ = 28.14 nM and 25.69 nM, respectively). Collectively, compound 18d can be used as a promising lead candidate for further optimization in the development of therapies targeting drug-resistant Trk mutants.

Diarylurea; Drug resistance; Molecular hybridization; Mutation; Tropomyosin receptor kinase inhibitors.