Project ID iCASE2023_01

ThemeCM-HD

Co Supervisor 1A Institute of Pharmaceutical Science, School of Cancer and Pharmaceutical ScienceWebsite

Co Supervisor 1B Cancer and Pharmaceutical SciencesWebsite

Partner Pheon Therapeutics Ltd

Explore efflux transporter-associated chemoresistance using a chemical biology approach and develop efflux resistant TOPO 1 inhibitors as ADC payloads

In this Pheon Therapeutics co-funded iCASE PhD project, the student will explore the phenomenon of efflux transporter-associated resistance and develop payloads that are less susceptible to efflux.

An appropriate choice of payload is critical to developing a successful antibody drug conjugate (ADC) for clinical development. However, 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 Rahman lab at King’s College London has developed a proprietary Efflux Resistance Breaker (ERB) Technology that allows modification of drugs to increase their cellular concentration to overcome chemoresistance. In this PhD project, the student will explore the phenomenon of efflux transporter-associated resistance and develop payloads that are less susceptible to efflux.

Aim of the Project: To explore the efflux transporter-associated chemoresistance using a chemical biology approach, and to develop ERB-modified topoisomerase I (TOPO I) inhibitors that can be further developed as ADC payloads.

Research Plan:
Year 1-2: Use computational techniques to study molecular level interactions of TOPO I inhibitor payloads (SN-38, Dxd etc.) with P-gp and BCRP efflux transporters, and design ERB-modified TOPO I inhibitors using Efflux Resistance Breaker Technology. Synthesis of 10-12 ERB-SN-38 and ERB-Dxd analogues with targeted modifications to provide SAR information.
Year 2-3: Molecular and cancer biology experiments to evaluate cytotoxicity in cancer stem cells and patient derived cells, evaluate Topo I inhibition, efflux liability and conduct developability assessment. Year 4: Select 3-4 candidates for ADC development. Evaluate the druggability of the selected ERB-modified payloads and obtain proof-of-concept in vivo data.

One representative publication from each co-supervisor:

Procopiou, G., Jackson, P. J., di Mascio, D., Auer, J. L., Pepper, C., Rahman, K. M., Fox, K. R., and Thurston, D. E. (2022) DNA sequence-selective GA cross-linking ADC payloads for use in solid tumour therapies, Communications Biology 5, 1-12.

Muliaditan, T., Opzoomer,J.W., Caron,J., Okesola, M., Kosti, P., Lall, S., Van Hemelrijck, M., Dazzi, F., Tutt, A., Grigoriadis, A., Gillett, C.E., Madden, S.F., Burchell, J.M., Kordasti, S., Diebold, S.S, Spicer,J.F., Arnold,J.N. {2018) Repurposing tin mesoporphyrin as an immune checkpoint inhibitor shows therapeutic efficacy in preclinical models of cancer. Clinical Cancer Research, 24:1617-
1628.