Abstract

One of the most common aberrations in human cancers is the overexpression of MYC, a master regulator transcription factor which functions in a heterodimer with the MYC-associated protein X (MAX) (Arvanitis & Felsher, 2006). Previously, it was shown that transduction of MYC caused resistance to PI3K inhibitor GDC-0941 (Muellner et al., 2011), and that the drug JQ1 inhibited MYC expression-induced PI3K rescue through JQ1’s inhibitory effects on the protein BRD4, which functions as a MYC enhancer (Stratikopoulos et al., 2015). Here we use novel small molecule modulators of MYC transcriptional activity, KI-MS1- 001 and KI-MS2-008, in a comparative study across three human cell lines against the aforementioned PI3K inhibitor GDC-0941 and BET inhibitor JQ1. Co-immunoprecipitation experiments between purified Streptavidin Binding Protein (SBP) tagged MYC, the SBP tag being used to purify the MYC from whole cell lysate, and pure MAX protein in the presence and absence of the compounds imply that the novel MAX modulator KI-MS2-008 does not disrupt the MYC/MAX heterodimer binding, but data also seemed inconclusive and more work needed to be done for a definitive answer. Cell viability assays in the breast lines HCC1599 and MDA-MB-468 confirms that KI-MS1-001 and KI-MS2-008 (in addition to JQ1 and GDC-0941) reduces the viability of these cell lines, more so than these modulators have in previous studies done by the Koehler lab in other lines, but the brain line U87MG showed non convergent IC50 values for all compounds. Experiments are currently being done to determine if the compounds lower MYC and MAX protein levels in a dose dependent fashion in these cell lines. While this work does not rigorously support the hypothesis
that the novel modulators would perform better than the other compounds, it contributes preliminary data for any future work the Koehler Lab will do that could more thoroughly test this hypothesis and optimize the modulators.