Explore efflux transporter-associated chemoresistance using a chemical biology approach and develop efflux resistant TOPO I inhibitors as ADC payloads

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Antibody-drug conjugates (ADCs) are an emerging class of cancer therapeutics that consist of a monoclonal antibody (mAb) connected to a cytotoxic drug via a linker. The antibody component determines the specificity of the ADC by binding to specific cell surface antigens, allowing selective targeting of certain cell types1. The main advantage of ADCs relative to conventional chemotherapeutics is an increased therapeutic window since the cell-targeting properties of antibodies decrease off-target toxicity2. The FDA has approved 11 ADCs to date with majority of them approved for the treatment of liquid tumours and only 3 ADCs have been approved for solid tumours. An appropriate choice of payload is critical to developing a successful ADC for clinical development3. Developability problems such as efflux liability, non-selective toxicity, chemoresistance, poor pharmacokinetic and pharmacodynamic profiles of existing payloads are leading to failures in clinical development. The majority of ADCs currently in clinical evaluation use microtubule inhibitors or DNA damaging agents as the payload, but more recently a significant number of ADCs with Topoisomerase I (TOPO I) inhibitors have entered clinical development due to the approval of Trodelvy R and Enhertu R which utilise Topoisomerase inhibitors SN-38 and Dxd as payloads (Figure 1), respectively4. Camptothecin and its derivatives bind to the TOPO 1/DNA complex to prevent reannealing, which can cause cell death due to the accumulation of partially cleaved DNA5. Both SN-38 and Dxd are Camptothecin analogues and are considered as next generation ADC payloads due to their relatively small-size and lower toxicity compared to microtubule inhibitors and DNA binding agents. However, both SN-38 and Dxd are efflux substrates of P-gp and BCRP efflux pumps which reduces their effectiveness, causing non-selective toxicity and often leading to chemoresistance particularly in cancer stem cells6,7. The Rahman lab at King's College London has developed a proprietary Efflux Resistance Breaker (ERB) Technology that allows modification of chemical scaffolds to reduce their efflux susceptibility while maintaining the on-target activity (Figure 2)8,9. This increases the intracellular concentration of the drugs which can overcome chemoresistance and reduce the likelihood of resistance emergence.The aim of this PhD project is to explore the phenomenon of efflux transporter-associated resistance using a chemical biology approach and produce ERB-modified TOPO I inhibitors that can be further developed as ADC payloads.