Structure-Activity Relationship of Indole-Tethered Pyrimidine Derivatives that Concurrently Inhibit Epidermal Growth...

Area of Science:

• Oncology
• Medicinal Chemistry
• Molecular Biology

Background:

• Antiangiogenic agents are crucial in advanced cancer management, often combined with chemotherapy.
• Targeting both epidermal growth factor receptor (EGFR) and angiokinases offers a potential alternative to combination therapies for EGFR-dependent cancers.

Purpose of the Study:

• To synthesize and characterize MKP101, a novel indole derivative of pazopanib, designed for dual inhibition of EGFR and angiokinases.
• To evaluate the anti-proliferative and anti-angiogenic effects of MKP101 on cancer cells and endothelial cells.

Main Methods:

• Bioisosteric replacement strategy was used to synthesize MKP101.
• In vitro assays were performed to determine IC50 values for EGFR and angiokinase inhibition.
• Functional assays assessed endothelial cell proliferation, tube formation, migration, and cancer cell proliferation.
• Molecular docking and structure-activity relationship (SAR) studies were conducted.

Main Results:

• MKP101 demonstrated potent inhibition of EGFR (IC50 = 43 nM) and angiokinases, comparable to pazopanib.
• MKP101 effectively inhibited vascular endothelial growth factor-induced endothelial cell functions and proliferation of EGFR-addicted HCC827 cancer cells.
• SAR studies revealed that substituents on the pyrimidine ring and the indole linkage influence selectivity for EGFR and VEGFR2.

Conclusions:

• MKP101 is a potent dual inhibitor of EGFR and angiokinases with significant anti-cancer and anti-angiogenic activity.
• The pyrimidine scaffold provides a basis for developing novel dual inhibitors with tunable selectivity.
• MKP101 represents a promising therapeutic candidate for EGFR-dependent cancers, potentially reducing the need for combination therapies.