Novel Highly Potent c-Met Degraders against a Broad Range of Cancers

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• The c-Met signaling pathway is a key driver in various cancers.
• Acquired resistance to c-Met inhibitors limits their clinical efficacy.
• Targeting c-Met remains a critical strategy for cancer therapy.

Purpose of the Study:

• To develop novel c-Met degraders to overcome acquired drug resistance.
• To evaluate the efficacy and pharmacokinetic properties of new c-Met degraders.
• To explore the potential of c-Met degraders in combination therapies.

Main Methods:

• Rational optimization of c-Met degraders (D19, D26, G4).
• Assessment of cell growth inhibition (IC50) and c-Met degradation (DC50) in cancer cells with MET alterations.
• Pharmacokinetic studies and in vivo efficacy evaluation using xenograft models.
• Testing against drug-resistant cell lines with specific MET mutations (D1228N, Y1230H).
• Evaluation of synergistic effects with other targeted therapies.

Main Results:

• Developed c-Met degraders D19, D26, and G4 with high potency (nanomolar IC50, picomolar DC50).
• Achieved >99% c-Met degradation via a Cullin-CRBN-dependent pathway.
• D19 and G4 demonstrated favorable pharmacokinetics and complete tumor inhibition in xenografts upon oral administration.
• D19 and G4 effectively inhibited tepotinib-resistant cells with MET mutations.
• Demonstrated synergistic anti-tumor effects of D19 in combination with EGFR/HER2, VEGFR, and BRAF inhibitors.

Conclusions:

• D19, D26, and G4 are potent c-Met degraders effective against MET-driven cancers.
• D19 and G4 exhibit promising pharmacokinetic profiles and in vivo efficacy.
• These novel degraders overcome resistance mechanisms associated with MET mutations.
• D19 and G4 represent promising therapeutic candidates for MET-driven malignancies, potentially in combination therapies.