Abstract 1227: New small molecules targeting MYC:MAX interactions that inhibits tumor cell growth in a MYC-dependent manner

Abstract

Abstract Deregulated expression of MYC family oncogenes MYC, MYCN and MYCL (here collectively referred to as MYC) occurs in many types of human tumors, and is often associated with aggressive tumor development and poor prognosis. In mouse tumor models, inactivation of MYC often leads to tumor regression with well-tolerated side effects, suggesting that MYC is a potential and suitable target for anti-cancer therapy. At present there are no drugs targeting MYC in the clinic, and transcription factors like MYC are considered difficult to target. However, MYC function is strictly dependent on interaction with cofactors, and targeting such interaction may be a plausible way to combat Myc. We have used cell-based screens utilizing Bimolecular Fluorescence Complementation (BiFC) and split Gaussia luciferase (G-Luc) to identify small molecule inhibitors of the interaction between MYC and its essential partner MAX. Several potent MYC:MAX interaction inhibitors have been identified in these screens and have been validated by other protein-protein interactions (PPI) assays such as in situ Proximity Ligation Assay (isPLA), Fluorescence Resonance Energy Transfer (FRET), Surface Plasmon Resonance (SPR) and coimmunoprecipitations. In general the identified molecules fall into two categories: those that inhibit MYC:MAX interactions not only in cells but also in vitro using purified MYC and MAX, and those that inhibit the interaction in cells but not in vitro, suggesting an indirect mode of action. Molecules of both categories inhibit cell growth and viability of a variety of tumor cells in culture with high efficacy in a MYC-dependent manner. So far, one of the molecules have been utilized for cancer treatment in mouse tumor models and found to significantly inhibit tumor growth and improve survival. These molecules have the potential to become important tools in the studies of MYC function in cells and in vivo as well as potentially basis for drug development for treatment of MYC-driven tumors. We have thus provided proof of principle that our screening systems are able to identify potent PPI inhibitors and we are at present setting up similar systems to screen for inhibitors of other MYC:cofactor interactions of relevance for specific tumor types. Citation Format: Alina Castell, Karin Ridderstråle, Qinzi Yan, Fan Zhang, Per Hydbring, Marcela Franco, Jacob Goodwin, Inga Müller, Siti Mariam Zakaria, Lars Johansson, Lars-Gunnar Larsson. New small molecules targeting MYC:MAX interactions that inhibits tumor cell growth in a MYC-dependent manner. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1227.