Novel PROTAC-based chemical biology approaches to induced protein knockdown across the proteome

DNA contains the information to produce a large number of different components within a human cell, including RNA and ultimately proteins, which altogether define how the cell functions. Abnormal behaviour of these components can alter cellular function, often resulting in disease. Conventional methods have modifed DNA or the coded RNA directly to alter the behaviour of cells. However, these approaches have documented limitations.

Removing “disease-causing proteins” is now becoming a possibility with the recent discovery of an exciting new class of chemicals, called PROteolysis TArgeting Chimeras (PROTACs). Importantly, PROTACS can be designed to bind proteins selectively and direct them to the cells own natural protein destruction machinery. We will build on the use of PROTACS and combine state-of-the-art chemical biology and genetic approaches to design a new set of universal protein binding “tool chemicals”.  Although beyond the scope of this programme, the tools generated will enable the study of the biological function of interesting proteins both physiologically and patho-physiologically.  The consequences of this are immense but could open up many new areas of disease biology research and ultimately unlock therapeutic strategies against a whole range of human proteins in an equally diverse range of human diseases.