Antibody–drug conjugates (ADCs) combine the targeting ability of antibodies with the potency of cytotoxic small molecules, offering precision treatment for cancer. However, resistance to ADCs can emerge when payloads are expelled by efflux transporters. To address this, our group is developing efflux-resistant payloads that retain potency inside cancer cells. One project uses a chemical biology approach to study how efflux pumps drive resistance to topoisomerase I inhibitors, enabling us to design modified payloads that are less susceptible to expulsion.
Another project focuses on the synthesis of entirely new classes of small-molecule payloads, optimised for stability, potency, and efficient tumour delivery. By combining medicinal chemistry with insights into transporter biology, we aim to design ADC payloads that bypass resistance mechanisms and maintain their ability to kill cancer cells. These projects are supported by the Medical Research Council, Pheon Therapeutics, and the China Scholarship Council. Together, they provide the foundation for next-generation ADCs that are more durable, effective, and broadly applicable across cancer types, with the potential to overcome limitations of current therapies and improve patient outcomes.