[Modality strategy in Eisai drug discovery: challenges toward next-generation therapeutics using proximity-inducing...

In recent years, the concept of "modality" has attracted significant attention in drug discovery, encompassing diverse approaches such as small molecules, antibodies, nucleic acids, and cell-based therapies. Eisai has leveraged its long-standing expertise in small-molecule drug design to focus on proximity-inducing compound (PIC), which induces novel pharmacological effects by bringing two distinct proteins into close proximity. PIC form ternary complexes between a target protein and an effector protein, enabling mechanisms such as targeted degradation, post-translational modification, and modulation of protein-protein interactions. This strategy allows intervention in previously "undruggable" targets that lack suitable binding pockets for conventional inhibitors. Among PIC, targeted protein degraders such as proteolysis targeting chimera (PROTAC) and molecular glue degrader (MGD) have advanced rapidly into clinical development worldwide. Eisai's entry into this field was driven by the discovery of the unique mechanism of action of Indisulam and E7820, which function as MGD to degrade RBM39 via DCAF15 recruitment. Building on this foundation, Eisai is pursuing tumor-selective strategies, including the development of a CEACAM6-targeted degrader antibody conjugate (DAC) and PROTAC utilizing tumor-selective E3 ligases. These approaches aim to achieve both efficacy and safety by restricting degradation activity to cancer cells. PIC represent a transformative modality that expands the druggable proteome and offers new therapeutic options for intractable diseases. This article outlines Eisai's efforts in PIC-based drug discovery, with a focus on targeted protein degradation and future perspectives.