Design, synthesis and biological activity of bicyclic carboxamide derivatives as TRK inhibitors

Area of Science:

• Oncology
• Medicinal Chemistry
• Molecular Biology

Background:

• Precision medicine tailors cancer treatment to individual genetic profiles, moving beyond traditional tissue-based classifications.
• Neurotrophin receptor tyrosine kinase (NTRK) gene alterations are actionable targets in various cancers, demonstrating significant therapeutic potential.
• Drug resistance remains a challenge in NTRK-targeted therapies, necessitating the development of novel inhibitors.

Purpose of the Study:

• To design and synthesize novel compounds targeting NTRK genes for cancer therapy.
• To evaluate the kinase inhibitory activity and cellular effects of newly synthesized compounds.
• To identify potential TRK inhibitors capable of overcoming acquired drug resistance.

Main Methods:

• Synthesis of twenty novel compounds in two distinct chemical categories.
• In vitro kinase activity assays to determine inhibitory concentrations (IC50) against wild-type and resistant TRKA variants.
• Cell viability assays using Ba/F3 cell lines engineered with NTRK1 fusions and resistance mutations.

Main Results:

• Compounds I-9 and I-10 exhibited potent inhibition of TRKA kinase activity (IC50 values in low nanomolar range).
• I-9 and I-10 demonstrated significant anti-proliferative effects in NTRK1-driven cancer cell lines.
• Both compounds showed improved activity against the TRKA G595R resistance mutation compared to the positive control LOXO-101.

Conclusions:

• Compounds I-9 and I-10 are identified as promising TRK inhibitors with potential to overcome drug resistance.
• These novel compounds warrant further investigation as targeted therapies for NTRK-altered cancers.
• The findings support the advancement of precision medicine strategies through the development of next-generation kinase inhibitors.