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Selective BRD4 degradation in pediatric leukemia

Date: -

Despite advances through cancer research that have improved outcomes for many children diagnosed with leukemia, subsets of the disease, including the high-risk MLL-rearranged acute myeloid leukemia (MLL-r AML), remain difficult to cure, establishing an area of significant unmet medical need. While many pediatric leukemias lack the multitude of mutations that are a hallmark of adult cancer, recurring abnormalities in proteins called transcription factors are quite common. Gene fusions, such as rearrangement of the MLL gene, mutation or amplification of a single transcriptional regulator often lead to the inappropriate regulation of the expression of genes in the cell that control cellular pathways involved in cell division and cell death, and thereby contribute to tumor development and cancer progression. One way to stop this abnormal gene expression program and to eradicate cancer cells would be to perturb a transcriptional regulator named BRD4. BRD4 is a member of the Bromodomain and Extra-Terminal motif (BET) family of proteins that can bind to chromatin and regulate gene expression. In leukemia, BRD4 has been shown to regulate cancer-promoting gene expression and to be an excellent target for the treatment of high-risk childhood cancers, including acute leukemia. Likewise, new drugs that inhibit BET proteins have been developed and shown to strongly downregulate expression of cancer-promoting transcription factors in acute leukemia in the laboratory. Clinical trials of BET inhibitors in adult patients are ongoing.

Unfortunately, current BET inhibitors target the entire BET family of proteins, including BRD2, 3, 4 and T, and toxicity has been reported in both preclinical and clinical research data. We hypothesize that targeting of BRD4 exclusively, may reduce this toxicity while still having a potent anti-cancer effect. As such, we have recently developed a molecule, ZXH-3-26, that can cause the selective degradation of the BRD4 protein. Not only does this new molecule discriminate between the BET family members but it also works via a new mechanism – protein degradation versus protein inhibition.

In order to better understand this new BRD4-selective degrader molecule, we propose to test ZXH-3-26 in laboratory models of pediatric acute leukemia first, to understand how it works to kill cancer cells and second, to compare it to currently available pan-BET inhibitors and degraders, which demonstrate toxicity and off-target effects. Finally, we plan to chemically optimize ZXH-3-26 so that it has improved properties of a drug that can be used to treat humans. This research will lay the foundation for a new therapy to treat children with cancer in clinical trials.

Investigator Address

Boston, MA
United States

Grant Program
Translational Research Program
Grant Subprogram
TRP Basic