BPI-28592 as a novel second generation inhibitor for NTRK fusion tumors

Area of Science:

• Oncology
• Molecular Biology
• Pharmacology

Background:

• Aberrant activation of tropomyosin receptor kinases (TRKs) drives neurotrophic tropomyosin receptor kinase (NTRK)-fusion cancers.
• Acquired resistance mutations limit the efficacy of first-generation TRK inhibitors.
• Developing novel inhibitors is crucial for treating resistant NTRK-fusion cancers.

Purpose of the Study:

• To introduce BPI-28592, a novel second-generation TRK inhibitor.
• To evaluate the efficacy of BPI-28592 against TRK fusion-positive cancers, including those with resistant mutations.
• To assess the potential of BPI-28592 to overcome drug resistance.

Main Methods:

• Docking simulations to predict drug-target interactions.
• Biochemical assays to determine inhibition and selectivity against TRKA, TRKB, and TRKC.
• In vitro studies assessing cell proliferation and TRK signaling.
• In vivo xenograft studies in TRK fusion-bearing models.
• Clinical evaluation in a patient with NTRK3 fusion-positive melanoma.

Main Results:

• Docking simulations suggested BPI-28592 has no steric hindrance with TRK mutants.
• BPI-28592 demonstrated potent inhibition and high selectivity for TRKA, TRKB, and TRKC.
• The inhibitor significantly reduced cancer cell proliferation and blocked TRK signaling pathways.
• BPI-28592 effectively suppressed tumor growth in preclinical xenograft models.
• Complete response was observed in a patient with malignant melanoma harboring an AP3S2-NTRK3 fusion.

Conclusions:

• BPI-28592 is a promising second-generation TRK inhibitor with broad efficacy against TRK fusion-positive cancers.
• Its design suggests potential to overcome acquired resistance mutations in TRK inhibitors.
• Clinical data supports the therapeutic potential of BPI-28592 in treating NTRK-fusion driven malignancies.