MD Anderson and Vanderbilt University join forces to develop epigenetic-based cancer therapies

Synergy through combined expertise

MD Anderson News Release 10/24/13

The University of Texas MD Anderson Cancer Center’s Institute for Applied Cancer Science (IACS) and Vanderbilt University will combine drug discovery and clinical translation efforts to accelerate the development of novel pharmacological inhibitors, initially focusing on bromodomain family of epigenetic regulators.

Bromodomains are commonly found in proteins that regulate chromatin structure: they bind to specific acetylated lysine motifs on histones “reading” the histone code and participate in translating this code into action by effecting chromatin remodeling and gene expression.  A detailed understanding of the biological function remains to be determined for most of the 63 human bromodomain containing proteins, yet several specific members of its family have been implicated in tumor growth. Recently, small molecule inhibitors of specific bromodomain proteins have been discovered and early clinical trials to treat cancer are already under way.

“When we realized that both of our drug discovery teams were pursuing the discovery of novel bromodomain inhibitors, we immediately sought to determine if we could join forces,” said Giulio Draetta M.D., Ph.D., IACS director, professor of Molecular and Cellular Oncology, and vice president for operations, Strategic Research Programs ad interim  “Our efforts have so much promise, but significant risk remains given the need to invest deeply into understanding the role of specific bromodomain proteins in normal and disease biology, while exploring unprecedented chemical space to develop inhibitors with the appropriate level of specificity.”

To address these challenges, a true risk and reward-sharing structure was developed to allow both sides to merge their portfolios and strengths. The comprehensive fragment- and structure-based design capabilities of the group at Vanderbilt will provide entry points into the most cancer relevant bromodomains identified through the deep biology insight of IACS.  Together, promising lead molecules will mature into clinical candidates that can be advanced into preclinical models and ultimately provide patients with new therapeutic options.

The collaboration combines the world-renowned fragment-based and structure-based drug design expertise of Stephen W. Fesik, Ph.D., professor of Biochemistry, Pharmacology and Chemistry, and Orrin H. Ingram II Chair in Cancer Research, and his laboratory at Vanderbilt University with IACS’ fully-integrated drug development and translational medicine capabilities.

Fesik takes an unbiased approach to identifying and optimizing novel chemical matter by screening libraries of small molecules called fragments and subsequently combining these fragments with weak affinities that bind to different sites to generate new chemical matter with higher affinity for the protein target. This approach of fragment-based drug design relies on a technique pioneered by Fesik, known as SAR by NMR (structure-activity relationship by nuclear magnetic resonance), which led to the discovery of inhibitors against the previously undruggable Bcl-2 family of proteins.

“I’m excited about this collaboration with the IACS team at MD Anderson,” says Fesik. “They have significant knowledge and experience in all aspects of the drug discovery process. I look forward to working with this outstanding group of scientists on targeting the bromodomains for cancer therapy.”