Abstract A17: Identification and characterization of small molecules targeting MYC-cofactor interactions

Abstract

Abstract Our aim is to develop specific inhibitors targeting the interaction between the oncoprotein/transcription factor MYC and its cofactors. MYC-family genes (MYC, MYCN, MYCL) are involved in over half of all cancers, including many childhood cancers such as neuroblastoma, medulloblastoma, leukemia and lymphoma, and is often strongly associated with poor prognosis. This emphasizes the need to identify clinically relevant MYC inhibitors. It regulates numerous genes involved in cell growth, metabolism, apoptosis, senescence and other processes. MYC is functionally dependent on interaction with the dimerization partner MAX and with several cofactors involved in different aspects of transcription regulation. Targeting such interactions with low Mw compounds is a plausible way to inhibit the transcriptional function of MYC. We have established several techniques to visualize MYC-cofactor interactions in living (BiFC, split Gaussia Luc) or fixed (isPLA) cells to screen small Mw compound libraries for MYC/cofactor-interaction inhibitors. In MYC/MAX BiFC and Gaussia Luc screens, 15 compounds were identified that directly or indirectly inhibit MYC/MAX interactions in cells. Several of these compounds including analogues are potent inhibitors of MYC/MYCN-dependent proliferation and transformation in neuroblastoma, leukemia/lymphoma and other cancer cells by inducing apoptosis or senescence. One of these, #2, and analogues completely inhibit MYC/MAX interactions in vitro by binding MYC. Another compound, 2XU, inhibit MYC/MAX interactions in sub-nanomolar concentration. We are evaluating the biological activities of these molecules further in different MYC-driven cell culture systems, and are elucidating their mechanisms of action by X-ray crystallography, FRET and SPR. In vivo studies with some of these molecules in mouse tumor models is ongoing. Furthermore, extended screens for finding molecules targeting MYC and other cofactor interactions, such as E3-ligases, are ongoing. The MYC inhibitors identified here have the potential to become important tools in the studies of MYC function in cells and in vivo as well as lead molecules for drug development for treatment of MYC-driven tumors. Citation Format: Alina Castell, Qinzi Yan, Karin Ridderstråle, Lars-Gunnar Larsson. Identification and characterization of small molecules targeting MYC-cofactor interactions. [abstract]. In: Proceedings of the AACR Special Conference on Myc: From Biology to Therapy; Jan 7-10, 2015; La Jolla, CA. Philadelphia (PA): AACR; Mol Cancer Res 2015;13(10 Suppl):Abstract nr A17.