Frontier Medicines Corporation has announced the publication of groundbreaking research in Structure, a Cell Press journal, demonstrating that DCAF2 can be harnessed as a novel E3 ligase for targeted protein degradation (TPD). The discovery represents a significant advancement in precision cancer treatment, particularly given DCAF2's frequent overexpression in various types of cancer.
Expanding the E3 Ligase Toolkit
The research addresses a critical limitation in the targeted protein degradation field. While more than 600 E3 ligases exist in the human proteome, only a few have been utilized for TPD applications, primarily VHL and cereblon.
"While more than 600 E3 ligases exist in the human proteome, we have utilized only a few so far, such as VHL and cereblon, for TPD," said Weiru Wang, Executive Director of Protein Sciences and Structural Biology and lead study author at Frontier Medicines. "Demonstrating that DCAF2 can be harnessed for this purpose is a major step forward for protein degradation, and for Frontier, as it aligns with our mission to unlock new ways to fight cancer and drug the undruggables."
Structural Insights Drive Discovery
The study leveraged Frontier's proprietary Frontier™ Platform alongside advanced cryogenic electron microscopy to present the first reported structures of the DCAF2 complex in both its apo and liganded states. This structural characterization was crucial to understanding how DCAF2 can be exploited for therapeutic purposes.
The research team discovered that DCAF2 can covalently and selectively bind to small molecules and cause the degradation of other proteins. This finding opens up a novel target site for TPD and creates new avenues for developing therapeutic bifunctional degraders and molecular glues that leverage DCAF2.
Implications for Cancer Treatment
DCAF2 presents particularly compelling opportunities for cancer therapy due to its frequent overexpression across various tumor types. This overexpression pattern suggests that DCAF2-based degraders could deliver tumor-targeted protein degradation while potentially sparing normal tissues.
The work expands possibilities for developing precision cancer treatments by selectively eliminating disease-causing proteins, including those previously considered undruggable. Wang emphasized that this discovery exemplifies how the company's platform enables deeper exploration of the proteome to develop novel approaches for targeting difficult proteins.
Platform-Enabled Discovery
The breakthrough was made possible through Frontier's chemoproteomics-powered drug discovery engine, which leverages covalent chemistry and machine learning to unlock difficult-to-drug disease-causing proteins. The platform's ability to identify covalent ligands that selectively target DCAF2 was key to the discovery.
Frontier Medicines is a clinical-stage precision medicine company focused on developing small molecule drugs against previously undruggable disease-causing targets, with initial focus areas in oncology and immunology. The company is advancing a diversified pipeline of precision medicines targeting critical drivers of cancer and high-value immunology programs.
