Alexander MacKerell, Ph.D. Ari Melnick, M.D. Gilbert Privé, Ph.D.
University of Maryland Weill Cornell Medical College University Health Network 

Therapeutic Targeting of Oncogenic Transcriptional Repressor Proteins

Abnormal gene expression is one of the hallmarks of all cancers in humans. Understanding the biological mechanisms that cause these abnormalities is essential in the effort to develop better treatments. In recent years one such mechanisms, called 'epigenetic' regulation has been found to play a fundamental role in suppressing genes that normally protect human cells from becoming cancerous. A major form of epigenetic regulation is mediated by a process called "DNA methylation' which consists of a chemical modification of genes that changes their function.

Research by Drs. Melnick, MacKerrell, and Prive have demonstrated that a newly discovered regulatory factor named "Kaiso' causes genes with abnormal DNA methylation to become suppressed. They explored the atomic resolution structure of Kaiso and identified a special 'pocket' on the surface of this factor. This pocket was required for Kaiso to attach to its key helper factors and carry out its gene suppressing functions. They showed that removing Kaiso from tumor cells allowed protective genes to be rescued and expressed. As a consequence, chemotherapy resistant tumor cells such as colon cancer cells became much more responsive to these drugs. They hypothesized that drugs designed to block the Kaiso 'pocket' might have a similar effect.

In preliminary studies, they used computational modeling to design small molecule compounds that could fit in the Kaiso pocket. When tested in cells, many of these compounds could in fact block the gene suppressing actions of Kaiso, and show that it is possible to design anti-Kaiso drugs. In this research program, investigators with special expertise in computer drug modeling, chemical creation of small molecule drugs, biochemistry and structural biology, and cancer biology and experimental therapeutics will form a multi-disciplinary team to design Kaiso inhibitor drugs. Over the course of the year-long funding period, they will use a series of state-of-the-art computational and biochemical tools to identify potential Kaiso inhibitor drugs and will rank these drugs according to their ability to specifically block Kaiso and kill colon cancer cells. The major outcome of the proposed one-year plan is the identification of lead compounds that will be subsequently improved and explored as a new class of anti-cancer agents. 


*Alexander MacKerell is also collaborating with Anthony Capobianco on another grant project, click here to learn more.