Development of Multi-Target Kinase Inhibitors for Overcoming Resistance in Cancer Therapy

Summary

Cancer remains a leading cause of death and a major global health burden. Dysregulation of Epidermal Growth Factor Receptor (EGFR) and Human Epidermal Growth Factor Receptor 2 (HER2) pathways is a hallmark of several aggressive cancers, making these receptors attractive therapeutic targets. Although multiple EGFR/HER2 inhibitors have been developed and are clinically used, their effectiveness is often compromised by the emergence of drug resistance. Among the most common resistance mechanisms are the EGFR T790M mutation and HER2 amplification, both associated with poor prognosis.

In previous work, our team identified compound 27b, a dual EGFR/HER2 inhibitor that demonstrated superior in vitro anticancer activity compared to the marketed drug Lapatinib, including activity against resistant cancer cell lines. However, 27b showed limited potency against the EGFR T790M mutation, the most prevalent resistance mechanism. This proposal aims to optimize 27b to achieve dual EGFR/HER2 inhibition with added activity against T790M, thereby addressing multiple resistance pathways.

The project will employ three iterative medicinal chemistry optimization cycles—design, synthesis, and biological evaluation—guided by molecular modelling and literature insights. These efforts are expected to yield a promising lead compound with broad-spectrum anticancer activity, supported by enzyme inhibition and cell-based assays. Anticipated deliverables include a potential patent application, a high-impact publication, and capacity building through postgraduate training.

This project aligns with Ain Shams University’s Strategic Plan by advancing scientific research, fostering innovation, and enhancing the university’s global ranking and reputation. It also contributes to Egypt’s Sustainability Plan 2023 through green chemistry practices, health innovation, and human capital development.

Achievements

List of Publications from the Project

Partners

Project Members

• Yassmina Wael Ahmed
• Sandra Nabil Mourad Milik

Project Leaders