Selective and Orally Bioavailable c-Met PROTACs for the Treatment of c-Met-Addicted Cancer

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• c-Met is a key therapeutic target in various cancers.
• Previous c-Met proteolysis-targeting chimeras (PROTACs) lacked detailed structure-activity relationship (SAR), selectivity, and pharmacokinetic data.
• Understanding these factors is crucial for developing effective c-Met-targeted therapies.

Purpose of the Study:

• To identify and characterize novel potent c-Met PROTACs.
• To investigate the SAR, degradation selectivity, and pharmacokinetic profiles of c-Met PROTACs.
• To evaluate the therapeutic potential of c-Met targeted degradation in preclinical cancer models.

Main Methods:

• Extensive SAR studies were conducted on PROTAC components: warheads, linkers, and E3 ligase ligands.
• A novel PROTAC, Met-DD4, was synthesized and evaluated for its ability to degrade c-Met.
• Cellular assays assessed c-Met degradation selectivity (DC50) and anti-cancer activity (IC50).
• In vivo studies in animal models evaluated oral bioavailability, c-Met degradation, tumor growth inhibition, and organ toxicity.

Main Results:

• A potent c-Met PROTAC, Met-DD4, was identified through comprehensive SAR studies.
• Met-DD4 demonstrated robust and selective c-Met degradation (DC50 = 6.21 nM).
• Met-DD4 exhibited significant anti-cancer activity against c-Met-addicted cancer cells (IC50 = 4.37 nM).
• In vivo studies confirmed Met-DD4's excellent oral bioavailability, effective c-Met degradation, tumor growth retardation, and minimal organ toxicity.

Conclusions:

• Targeted degradation of c-Met is a viable and promising therapeutic strategy for c-Met-addicted cancers.
• Met-DD4 represents a novel lead compound with potential for clinical translation in c-Met-targeted cancer therapy.
• This study provides valuable insights into the SAR and properties of c-Met PROTACs.