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

Area of Science:

• Oncology
• Medicinal Chemistry
• Molecular Biology

Background:

• Tropomyosin receptor kinases (TRKs) are key cancer targets, with FDA-approved drugs like Larotrectinib and Entrectinib showing promise.
• Acquired resistance to TRK inhibitors, often caused by secondary mutations, limits therapeutic efficacy, creating a clinical need for new treatments.

Purpose of the Study:

• To design and synthesize novel diarylurea derivatives as potential type II TRK inhibitors.
• To evaluate the efficacy of these compounds against wild-type and drug-resistant TRK mutations.

Main Methods:

• Employed a molecular hybridization strategy to design novel diarylurea derivatives.
• Assessed inhibitory activity against TRKA (WT/G595R/G667C) using IC50 values.
• Evaluated antiproliferative effects on BaF3-LMNA-TRKA (G595R/G667C) cell lines.

Main Results:

• Compound 18d demonstrated potent inhibition of TRKA (WT/G595R/G667C) with low nanomolar IC50 values.
• 18d exhibited superior antiproliferative activity against resistant cell lines compared to Repotrectinib.
• Specifically, 18d showed IC50 values of 23.76 nM and 0.33 nM against BaF3-LMNA-TRKA(G595R) and BaF3-LMNA-TRKA(G667C) cell lines, respectively.

Conclusions:

• Compound 18d is a potent TRK inhibitor effective against drug-resistant mutants.
• 18d represents a promising lead candidate for developing therapies targeting TRK-mutant cancers with acquired resistance.