Dana-Farber Investigators Formulate First IRF Degrader with Potential for Multiple Myeloma

RESEARCH SUMMARY

Study Title: Pharmacological Targeting of IRF4 as a Therapeutic Strategy for Multiple Myeloma

Publication: Nature Chemical Biology

Dana-Farber Cancer Institute authors: Irene Ghobrial, MD, Jun Qi, PhD 

Summary: A transcription factor called interferon regulatory factor 4 (IRF4) is a top target for multiple myeloma because of its role as an oncogene. However, transcription factors, which regulate genes and genetic programs in cells, are often thought to be “undruggable” because they lack deep pockets for drugs to bind to. In new research, Dana-Farber Cancer Institute investigators led by Drs. Ghobrial and Qi have discovered and designed a compound that binds to IRF4 and induces its degradation by a natural cellular recycling system. 

The team was inspired by studies of genetic knockouts of IRF4 that resulted in cancer cell death in models of multiple myeloma. To more closely mimic a knockout of IRF4, they pursued a protein degrader rather than a small molecule inhibitor. Using high throughput screening, the team discovered and refined a small molecule that binds to a pocket on IRF4. They then converted that small molecule into a compound that acts as a selective degrader called dIRF4-2 by linking it to an E3 ligase binder to flag IRF4 for degradation by the proteasome. Tests in models of multiple myeloma showed that dIRF4-2 resulted in down-regulation of cancer related genetic programs in myeloma cells and dramatically reduced proliferation of myeloma cells. 

The team sees dIRF4-2 as a starting point for development of IRF4 degraders for the treatment of multiple myeloma and sees an opportunity for leveraging their methodology to find ways to target other IRF transcription factors that play roles in lymphoma, multiple myeloma, and leukemia and beyond.

Significance: This study reports the first potent and selective compound to target IRF4, a transcription factor known to drive multiple myeloma, and validates degradation of IRF4 as a potential approach to the treatment of multiple myeloma. More research is required to develop and validate a solution that is ready for clinical testing. The team’s multi-discipliniary drug discovery methodology might also be an effective approach to finding ways to target the transcription factors that play a role in cancers in general.

Funding: The Linde Family Foundation, Novartis Institutes for BioMedical Research, and Blood Cancer United.