Streamlining PROTAC Discovery

How a direct-to-biology approach can streamline the DMTA cycle in PROTAC® discovery

Novel targeted protein degrader (TPD) modalities, including molecular glues and PROTACs, are rapidly reshaping approaches to difficult therapeutic targets. The FDA approval of vepdegestrant in May 2026, the first PROTAC therapy for ESR1-mutated ER+/HER2- advanced breast cancer, marks a pivotal milestone, validating TPD as a strategy for previously undruggable targets.

However, the design of TPD molecules can be challenging for multiple reasons, including complex structure-property relationships, extensive reliance on cell‑based assays, and time-consuming linker optimization. These issues can stretch design-make-test-analyze (DMTA) cycles to months and consume substantial synthetic and analytical resources.

The direct-to-biology (D2B) approach is a practical way to address these bottlenecks, enabling rapid exploration of linker and exit‑vector space and delivery of rich cell-based degradation data within days rather than weeks and months.

Learn about the principles of using D2B in TPD and PROTAC discovery programs and how this approach provides significant efficiency gains over traditional workflows. We explore recent literature and real-world examples to illustrate improvements in speed, efficiency, and sustainability, and highlight practical considerations for scientists interested in adopting D2B in their own programs.

_{PROTAC® is a registered trademark of Arvinas}