Unlocking new drug targets through antibody-targeted protein degradation

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Targeting protein degradation with Proteolysis-Targeting Chimeras (PROTACs) is an area of great current interest in drug discovery. Nevertheless, although PROTACs can be highly effective against a wide variety of targets, most degraders reported to date display limited intrinsic tissue selectivity, and do not discriminate between cells of different types. We recently reported a novel strategy for selective protein degradation in a specific cell type with one of the first antibody-PROTAC conjugates, demonstrating antigen-dependent degradation of a target protein specifically in HER2-positive breast cancer cells (ACS Chem. Biol. 2020, 1306). These studies demonstrated proof-of-concept for tissue-specific degradation, overcoming limitations of PROTAC selectivity, with significant potential for application to novel targets.This project brings together innovations in targeted protein degradation with the world-leading expertise of ADC Therapeutics in preclinical and clinical antibody-drug conjugate (ADC) development (https://www.adctherapeutics.com/) to discover a new generation of targeted protein degraders as novel ADC payloads. You will push the boundaries of ADC design, exploiting new modalities including high-affinity peptide-based degraders for intractable targets, molecular glues, and autophagy- or lysosome-targeting compounds. You will combine these payloads with clinical grade ADC linker design and monoclonal antibodies to enable precise release of degraders targeted to specific tissue types across a range of disease indications, with an initial focus on cancer.This studentship would suit a talented and motivated chemist or chemical biologist who is passionate about research at the interface with biomedicine, and with a strong interest in targeted protein degradation and novel drug modalities. Applicants should have an outstanding academic background in chemistry or a closely related area. Training will be provided in all relevant areas (synthesis, bioconjugations, cell biology, etc.), but previous lab experience in synthesis, chemical biology or protein chemistry would an advantage. The successful applicant will undertake research at the £170M state-of-the-art Molecular Sciences Research Hub and with ADC Therapeutics at the I-HUB, co-located at Imperial's new White City Campus.