Although the conventional paradigm explaining the mechanism of small molecule drugs is that they act as modulators of single protein targets, more complex mechanisms of action are needed to explain the behavior of many of those compounds. It is now widely appreciated that some small molecule drugs act by inducing proximity between two proteins which otherwise would not interact, resulting in various downstream effects. Indeed, this effect explains the mechanism of action for naturally occurring small molecules such as the plant hormone families of auxins and jasmonates, and the commonly used drugs rapamycin and cyclosporin. In 2010, it was discovered that induced proximity was the primary mechanism of action of the drug thalidomide, which acts by inducing novel protein interactions with the E3 ligase cereblon. The discovery of thalidomide’s mechanism of action accelerated research into the development of engineered bifunctional molecules to modulate and control induced proximity as a means to study cell biology and develop therapeutics.
Despite these advances, a great deal remains to be learned about the generalizable rules and scope of induced proximity. Much of the work has focused on developing PROTACs (proteolysis targeting chimeras), heterobifunctional molecules which bring together E3 ligases with various neosubstrates for protein degradation. The early examples of PROTACS contained E3 ligase-binding portions which were serendipitously discovered instead of through rational drug design. Other types of induced proximity with different protein effectors are in their infancy, although they hold tremendous potential. Finally, a major challenge is the protein pair problem: how to identify which protein to bring to a target to achieve a desired biological effect. In other words, out of the ~20,000 proteins encoded in the human genome, which one is the best option to modulate a target therapeutically?
In this ASPIRE award, Mikko Taipale, Daniel Durocher, and Frank Sicheri are establishing a proof-of-concept method to assay the human proteome in an unbiased manner to modulate a target protein of interest. They will do so through a novel screening platform engineered to induce proximity between proteins followed by a functional readout. In their screens, they will probe the induced stability of the enzyme PTEN, and inhibition of the phosphatase PTPN2, both of which are high-value oncology targets. If successful, these studies will substantially enhance our understanding of engineering induced proximity, expand the scope of druggable targets, and start moving induced proximity into other fields beyond protein degradation with wide therapeutic potential in oncology and beyond.