Chemical modulation of bromodomain function in development and disease

Acute myeloid leukemia (AML) is an aggressive cancer of the blood. Mutations in blood-forming stem cells in the bone marrow lead to the uncontrolled formation of abnormal cells, which interfere with normal blood function. In many cases the only hope, if any, is a bone marrow transplant.

The project focuses on a class of proteins with functional sub-structures called bromodomains. These domains bind to epigenetic marks, which label genes as on or off, on the proteins packaging DNA. Once bound, other parts of these bromodomain-containing proteins can add more of these epigenetic marks or directly activate nearby genes to regulate cell activity.

Errors in this regulation of gene activation are one of the reasons blood-forming stem cells start multiplying uncontrollably to cause AML, and many other cancers also show aberrant epigenetic modifications. For this reason bromodomains are a good target for new types of therapy: If they’re blocked with small, synthetic molecules, the undesired gene activation can be stopped.

To do this the chemists on the team will synthesize potential bromodomain inhibitors designed by the computational biologists in computer simulations. Then the biochemists can test their ability to block bromodomains in the test tube. Next, the epigeneticists will test their function in embryonic stem cells derived from mice, using genome-wide analysis to show how the inhibitors change epigenetic control of genes.

Finally, the developmental biologists will investigate suitable lead substances to determine their effects on the blood-forming system of zebrafish, an important research model where each type of cell can be labelled and tracked microscopically in living animals. Ultimately this should produce promising active agents that can be tested on humans in clinical trials.

The project involves four research groups, including Cristina Nevado in chemistry and Amedeo Caflisch in biochemistry. They’re joined by epigeneticists from the group of Tuncay Baubec (Department of Molecular Mechanisms of Disease) and developmental biologists from Christian Mosimann’s team. Together they’re addressing the question of how certain proteins switch genes on and off.