Report
Teaser, summary, work performed and final results
Periodic Reporting for period 1 - HOXA9 degradome (Deciphering the machinery involved in stability of the transcription factor HOXA9.)
Teaser
Transcription factors – the master regulators of cell function – are often mutated or abnormally expressed in cancer. For a long time however, it has been difficult to target these proteins due to the lack of an appropriate drug binding site. More recently, it has been...
Summary
Transcription factors – the master regulators of cell function – are often mutated or abnormally expressed in cancer. For a long time however, it has been difficult to target these proteins due to the lack of an appropriate drug binding site. More recently, it has been discovered that drugs such as thalidomide (and its related analogues pomalidomide and lenalidomide) can induce rapid and specific degradation of transcription factors that drive a number of blood cancers, including multiple myeloma and the pre-leukemic myelodysplastic syndrome (MDS).
My project seeks to characterize the various means by which drug-induced degradation occurs, with the goal of ultimately designing a new generation of ‘degrader’ compounds. Drug-induced protein degradation holds promise for future targeted cancer treatments. This may ultimately result in reduced death rates for cancer patients, relieving the economic burden on the health care system in Europe.
Specifically, my project aims to characterize diverse aspects of drug-induced degradation by unbiased functional genomic approaches, which in the future will enable the design of a new generation of “degrader†compounds.
Work performed
Drug-induced protein degradation relies on multiple components of the cell’s degradation machinery, i.e. the ubiquitin-proteasome system. We have developed tools that enable the unbiased identification of E3 ligase adaptors necessary for drug-induced degradation. We optimized and tested this approach using four degrader compounds. We identified cereblon (CRBN) as the main E3 ligase adaptor for pomalidomide-induced degradation of IKZF3 and CC885-induced degradation of GSPT1, and found that the DCAF15 adaptor and VHL were required for indisulam-induced degradation of RBM39 and BRD4-induced degradation of MZ1, respectively. These findings validated that our functional genomics pipeline can dissect the molecular machinery involved in drug-induced degradation.
To investigate drug-induced degradation by two novel IMiD derivatives for the whole family of transcription factors, we employed a library of 6572 C2H2 zinc fingers and fused them to the green fluorescent protein. This enabled us to identify zinc finger proteins degraded by the IMiDs compounds. I focused my attention on two novel IMiD derivatives, CC-122 (avadomide) and CC-220 (iberdomide). In summary, CC-122 and CC-220 resulted in the degradation of distinct and unique patterns of C2H2 zinc fingers. The zinc finger ZKSC5 was exclusively degraded by CC-122, while the zinc finger IKZF2/4 was exclusively degraded by CC-220.
Final results
To date, the functional genomic pipeline I have developed has enabled us to characterize the machinery involved in drug-induced degradation by four compounds. A similar approach is currently being employed for less well-characterized compounds.
Using this approach, I aim to identify and characterize novel compounds that may result in specific drug-induced degradation. This finding may ultimately be the basis for the development of a new class of degrader compounds, with the goal of redesigning these to degrade clinically relevant targets.
In my future research, I hope to understand how E3 ligase adaptors choose a particular target for degradation and how this could be modulated using a small molecule to achieve clinical benefit. I hope this approach will ultimately revolutionize the future of targeted drug therapy.
Website & more info
More info: https://ebertlab.dana-farber.org/.