Selective Aurora A-TPX2 Interaction Inhibitors Have In Vivo Efficacy as Targeted Antimitotic Agents

Area of Science:

• Molecular Biology
• Cancer Research
• Drug Discovery

Background:

• Aurora A kinase is overexpressed in cancers, promoting genome instability and chemotherapy resistance.
• Aurora A's function is regulated by its interaction with the spindle assembly factor TPX2.
• Targeting protein-protein interactions (PPIs) is an emerging strategy in cancer therapy.

Purpose of the Study:

• To develop small molecule inhibitors of the Aurora A-TPX2 PPI using fragment-based, structure-guided approaches.
• To characterize the lead compound CAM2602 for its efficacy, specificity, and mechanism of action.
• To evaluate the therapeutic potential of targeting the Aurora A-TPX2 PPI in preclinical cancer models.

Main Methods:

• Fragment-based and structure-guided drug discovery.
• Biochemical assays to determine binding affinity and inhibition of Aurora A-TPX2 interaction.
• In vivo studies using tumor xenografts to assess efficacy and pharmacodynamics.
• Combination studies with paclitaxel in pancreatic cancer models.

Main Results:

• Developed CAM2602, a potent inhibitor of the Aurora A-TPX2 PPI with 19 nM affinity for Aurora A.
• CAM2602 demonstrated oral bioavailability, biomarker modulation, and significant tumor growth inhibition in xenografts.
• CAM2602 exhibits high specificity for Aurora A over Aurora B and acts via a novel mechanism.
• CAM2602 synergized with paclitaxel to suppress pancreatic cancer cell growth, consistent with Aurora A's role in taxane resistance.

Conclusions:

• Targeting the Aurora A-TPX2 PPI with small molecules like CAM2602 is a viable therapeutic strategy for cancer.
• CAM2602 represents a promising drug candidate with potential clinical utility.
• Inhibiting Aurora A-TPX2 interaction offers a novel approach to overcome chemotherapy resistance.