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[Modality strategy in Eisai drug discovery: challenges toward next-generation therapeutics using proximity-inducing
1Tsukuba Medicinal Chemistry, Integrated Chemistry, DHBL, Eisai.
Summary
Eisai is advancing proximity-inducing compounds (PIC) for drug discovery, focusing on targeted protein degraders like PROTAC and molecular glues to address previously undruggable targets and improve cancer therapy. These novel modalities expand therapeutic options for difficult diseases.
Area of Science:
- Drug discovery and development
- Molecular pharmacology
- Oncology therapeutics
Background:
- The concept of "modality" in drug discovery is expanding beyond traditional approaches.
- Proximity-inducing compounds (PIC) create ternary complexes to modulate protein function.
- Targeted protein degraders, including proteolysis targeting chimera (PROTAC) and molecular glue degraders (MGD), are emerging as powerful therapeutic strategies.
Purpose of the Study:
- To outline Eisai's efforts in proximity-inducing compound (PIC) based drug discovery.
- To highlight the application of PIC in targeted protein degradation for novel therapeutic interventions.
- To discuss future perspectives of PIC in expanding the druggable proteome.
Main Methods:
- Leveraging expertise in small-molecule drug design to develop PIC.
- Investigating molecular glue degraders (MGD) such as Indisulam and E7820 for RBM39 degradation via DCAF15.
- Developing tumor-selective strategies including degrader antibody conjugates (DAC) and PROTACs utilizing tumor-selective E3 ligases.
Main Results:
- Eisai's MGDs, Indisulam and E7820, demonstrate RBM39 degradation through DCAF15 recruitment.
- Development of novel tumor-selective PIC strategies targeting CEACAM6 and employing tumor-specific E3 ligases.
- PIC strategy enables intervention against previously undruggable targets.
Conclusions:
- Proximity-inducing compounds (PIC) represent a transformative modality in drug discovery.
- Targeted protein degradation via PIC expands the druggable proteome and offers new therapeutic options for intractable diseases.
- Eisai's focus on PIC, particularly targeted protein degraders, aims to enhance both efficacy and safety in cancer treatment.
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