Abstract 3693: Small molecule microarray screens for inhibitors of oncogenic ETS factors

Abstract

Abstract Members of the ETS transcription factors family are involved in many cancers and are often targeted by translocation events that result in oncogenic gene fusions or dysregulated ETS factor expression. For example, the vast majority of prostate cancers harbor translocations involving the ETS factors ERG, ETV1 and ETV4 (most commonly, these are fused to the TMPRSS2 androgen-regulated gene or other house keeping genes). Overexpression of ETS factor gene fusions can induce or sustain malignant characteristics of cancer cells such as survival or invasiveness. However transcription factors have often been deemed “undruggable” by conventional approaches. The focus of this project is to employ novel screening approaches to identify and characterize small molecules that are able to bind and modulate the biological function of oncogenic ETS factors. Toward this end, we have performed Small Molecule Microarray (SMM) screens that involve a total of 80,000 distinct small molecules spanning several categories, including diversity-oriented synthesis (DOS) products, natural products, and other biologically active chemotypes. The SMM screens identified six compound that selectively bind the ETS factor ETV1 with a stringent Zscore. Two of these compounds have shown inhibitory activity in an ETV1-specific promoter-induced luciferase system. Surface Plasmon Resonance analysis has confirmed that each of the two lead compounds binds ETV1 directly, with one compound showing submicromolar binding kinetics. This compound in particular was able to reduce the expression of several ETV1 downstream targets such as MMP1 and MMP7. These efforts suggest that we have identified novel small molecule “perturbagens” of ETV1, an oncogenic ETS transcription factor. More generally, our results suggest that SMM-based screens may offer a robust approach to identify novel compounds that bind and perturb the function of cancer-associated proteins deemed poorly “druggable” by conventional methods. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3693.