Before the discovery of the genetic causes of cancer, the concept of taming cancer cells by triggering their differentiation attracted a lot of research activity. Compounds such as dimethylsulfoxide (DMSO) and hexamethylene bisacetamide (HMBA) are still used to induce differentiation in experimental systems but the mechanisms of action have remained unclear. Here we demonstrate that HMBA, a compound that was used in clinical trials against cancer over twenty-five years ago, is a selective bromodomain inhibitor. Biochemical and structural studies reveal that HMBA has affinity for the second bromodomain of BET proteins. Accordingly, we show that both HMBA and the prototype BET inhibitor JQ1 cause mouse erythroleukemia differentiation. As expected from a BET inhibitor, HMBA causes massive transcriptional changes, displacement of BET proteins from chromatin, cell cycle arrest and apoptosis of Myc-induced B-cell lymphoma. We show for the first time that HMBA can be successfully used to treat mice carrying Myc-driven B-cell lymphoma. This study provides a historical link between clinical trials conducted in the 1990s and ongoing BET inhibitor clinical trials, predicting issues with patient selection and response rates. The structural data also suggest starting-points for the creation of BD2-selective BET inhibitors.
- Received October 5, 2015.
- Revision received December 17, 2015.
- Accepted February 18, 2016.
- Copyright ©2016, American Association for Cancer Research.