Recent advances in cancer biology have led to the identification of more cancer-causing proteins for targeted cancer therapy. However, despite these discoveries, we still face significant challenges because many proteins that promote cancer growth cannot be targeted by current approach. Traditional drugs work by fitting into specific pockets on proteins, but many cancer-related proteins lack these pockets. Molecular glue degraders have emerged as a promising solution for targeting these difficult proteins. These compounds work by binding two proteins together: one that needs to be eliminated (the target) and another that marks it for destruction (E3 ligase, the body's natural protein-disposa...

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Recent advances in cancer biology have led to the identification of more cancer-causing proteins for targeted cancer therapy. However, despite these discoveries, we still face significant challenges because many proteins that promote cancer growth cannot be targeted by current approach. Traditional drugs work by fitting into specific pockets on proteins, but many cancer-related proteins lack these pockets. Molecular glue degraders have emerged as a promising solution for targeting these difficult proteins. These compounds work by binding two proteins together: one that needs to be eliminated (the target) and another that marks it for destruction (E3 ligase, the body's natural protein-disposal system). While these two proteins do not naturally interact, their surfaces are highly complementary, and molecular glues provide the additional binding energy needed to stabilize this interaction. This "induced" interaction redirects the E3 ligase to recognize and break down the disease-causing target protein. However, most discoveries of molecular glues have been serendipitous, making the use of molecular glues in cancer therapy a significant challenge despite their high potential. To address this challenge, we have developed a novel approach to systematically identify molecular glue degraders. With this approach, we propose to develop a novel molecular glue degrader targeting DDX18. DDX18 has not been targeted due to the lack of suitable chemical compounds despite being implicated in the progression of pancreatic ductal adenocarcinoma (PDAC) and poor therapy outcomes. A molecular glue degrader targeting DDX18 will provide a new way to overcome PDAC, a cancer that has been particularly difficult to treat effectively. Additionally, the developed platform is broadly applicable for developing molecular glue degraders. This holds significant promise for enhancing cancer therapeutics by providing new avenues for targeting previously untargeted proteins. 1

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