Development and Validation of Selective Small Molecule ETS Factor Inhibitors for Prostate Cancer—Understanding Gene Activity that Likely Causes Up to 60 Percent of Prostate Cancer Cases Can Open Door to New Drug Development—Another Approach

Co-Investigator: Towia Libermann, PhD–Associate Professor, Medicine, Director, Genomics and Proteomics, Beth Israel Deaconess Medical Center, Harvard Medical School, Director, Dana Farber Cancer Institute Cancer Proteomics Core, Harvard Medical School

Co-Investigator: Alan Rigby, PhD–Assistant Professor, Medicine, Director, Program in Drug Discovery and Target Validation, Beth Israel Deaconess Medical Center, Harvard Medical School

The genetic alteration present in 40-60% of prostate cancer cases gives rise to expression of ETS factors that drive the initiation and progression of prostate cancer. Identification of the ETS factor binding sites on DNA is the first step in selecting candidate inhibitors of the highly carcinogenic event. In contrast to Dr. Barbara Graves’ Creativity Award, where advanced molecular biology biotechnologies will be used to identify these sites, Drs. Libermann and Rigby will use state-of-the-art computer-aided drug design methods and biocomputational models to model the structure of these sites. In fact, this work has already identified a series of candidate lead compounds that block ETS binding to DNA. If successful, this work could generate drug candidates to block prostate cancer progression.

Progress Report:

One of the most significant breakthroughs for prostate cancer is the identification of genefusions. Gene fusions occur when two genes that are normally found in different regions of DNA rearrange and are erroneously juxtaposed. In cancer these gene fusions can be central drivers of the disease. Many of the known gene fusions described in prostate cancer involve the ETS family of proteins, which include ERG, ETV1, ETV4 and ETV5. ETS proteins elicit their activity by binding to DNA. These findings provoked the hypothesis that ETS factors are novel therapeutic targets in prostate cancer patients.

In this creative award, Drs. Libermann and Rigby have applied a powerful innovative state-of-the-art computational approach combined with medicinal chemistry to discover and validate new first-in-class small molecules that selectively target the most prominent ETS factor in prostate cancer, ERG. They have identified several lead small molecule compounds that specifically bind to the essential protein domain of ERG which inhibits DNA binding and subsequent cancer-causing downstream effects of ERG in prostate cancer cells. Using cell based assays combined with gene expression analysis to confirm the efficacy of selected ERG inhibitors the team has prioritized their lead compounds. The hope is that these small molecules which inhibit ERG will provide promising innovative therapies for prostate cancer patients, which may have therapeutic benefits alone or in combination with standard-of-care therapeutic approaches.