Abstract 3952: Selective high affinity MYC-binding compound inhibits MYC-MAX interaction and MYC-dependent tumor cell growth

Abstract

Abstract The MYC family oncoproteins/transcription factors MYC, MYCN and MYCL (here referred to as MYC) are key players in tumor development and are particularly associated with aggressive disease and poor prognosis. Efficient and specific MYC-targeting drugs are therefore highly warranted, but no such drugs are available in the clinic at present. MYC is strictly dependent on heterodimerization with MAX for activation of transcription. In a cell-based Bimolecular Fluorescence Complementation protein-protein interaction screen for small molecule inhibitors we identified a molecule that exhibits strong selective inhibition of MYC-MAX interaction in cells as validated by Gaussia luciferase protein complementation assay, coimmunoprecipitation and in situ proximity ligation (isPLA) assay, reaching an IC50 at single-digit micromolar concentrations. The molecule was shown to inhibit MYC-MAX interactions in a biochemical FRET assay and binds selectively to the MYC bHLHZip domain with affinity in the single digit micromolar range as demonstrated by Microscale Thermophoresis and Surface Plasmon Resonance. Further, within the same concentration range, this molecule blocks MYC-driven transcription and efficiently inhibits tumor cell growth in a MYC-dependent manner, but spares normal cells. Moreover, the growth inhibitory responses to the molecule correlated significantly with MYC expression levels in a cohort of 60 human tumor cell lines. Importantly, utilizing a mouse tumor model of MYCN-amplified neuroblastoma, treatment with the molecule resulted in significant inhibition of the MYC-MAX interaction in tumor tissue, as shown by isPLA, and massive induction of apoptosis in the tumors. Since this molecule, unlike many experimental MYC inhibitors, is selective, has high affinity for MYC, has high efficacy in cells, reaches its target in vivo and does not affect MYC expression levels, it can be used as a chemical tool to specifically study the role of the MYC-MAX complex in MYC biology in normal and cancerous cells, and it has potential for drug development. Citation Format: Alina Castell, Qinzi Yan, Karin Fawkner, Per Hydbring, Fan Zhang, Vasiliki Verschut, Marcela Franco, Giovanna Zinzalla, Lars-Gunnar Larsson. Selective high affinity MYC-binding compound inhibits MYC-MAX interaction and MYC-dependent tumor cell growth [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3952.