The field of functional genomics, which associates genetic variants with function at a massive scale, has uncovered a new frontier of highly validated and high-value drug targets. For example, there is extensive evidence that amplification or mutation of specific proteins constitutes a direct mechanistic driver of cancer progression, and these variants are correspondingly highly correlated with poor clinical outcome and therapy resistance. Emerging targets include well-known oncogenic transcription factors (e.g. Myc) or signalling hubs (e.g. K-Ras) which have become an intense focus for drug discovery; however, the majority have also proven persistently very difficult or impossible to drug through conventional discovery approaches. These next generation high-value targets are often termed ‘intractable’ or ‘undruggable’ and present a challenge at the cutting-edge of drug discovery science.
You will develop a new and universal chemical proteomic technology platform which can comprehensively explore and interrogate the interactome for any intractable target in living cancer cells. You will thereby unlock the ability to screen large compound libraries for small molecules which selectively target protein complexes regulating each intractable target, revealing starting points for new classes of medicines. We anticipate that you will discover compounds which exploit novel and cancer-specific modes of action which can only be discovered in the context of an intact cell, including so-called ‘molecular glue’ modalities which degrade or stabilize novel or native complexes with intractable targets. You will develop a deep and wide range of expertise in this essential area for future drug discovery, including chemical probe design, chemical proteomics, proximity labelling, high-throughput screening and CRISPR-Cas technologies.
This project would suit a candidate with a passion for developing new approaches for drug discovery, through applying chemistry to understand complex biological systems and cell biology. Prior experience in a multidisciplinary research environment, for example in chemical biology, would be an advantage. This project will be supervised by Prof Ed Tate (http://www.imperial.ac.uk/tate-group/), Dr Emanuela Cuomo (AstraZeneca, Cambridge UK), and Dr Marco Di Antonio (https://www.imperial.ac.uk/diantonio-research-group/), in state-of-the-art chemical biology labs in the £170M Molecular Sciences Research Hub at Imperial White City campus.