Abstract IA15: Novel approaches for targeting MYC

The MYC family (c-, L-, and N-MYC) is one of the most important groups of proteins in human cancer. More than 50% of all malignancies overexpress at least one MYC family member, and estimates suggest that upwards of 100,000 Americans die from cancer every year as a result of inappropriate MYC expression or activity. Preclinical mouse models have demonstrated that perturbing MYC function in preexisting cancers promotes frank tumor regression, establishing MYC proteins as bonafide and high-value targets for discovery of broadly effective anti-cancer therapies.

Despite the potential of MYC inhibitors to impact cancer therapy, efforts to discover MYC inhibitors are stymied by numerous factors, including an absence of MYC interaction partners with characteristics that make them amenable to drug discovery efforts. The best understood MYC interaction partner, MAX, is required for MYC to assemble a competent DNA-binding module and would theoretically be a superb target for anti-MYC therapies. The MYC–MAX interaction, however, encompasses more that 1800 Å2 of buried protein surface, making it difficult to effectively disrupt by a small molecule with drug-like properties. Breaking the stalemate in drugging MYC requires a fresh perspective on how MYC functions and where the vulnerabilities in its molecular mechanisms of action lie.

Structure-function studies have delineated a potent activation domain at the amino-terminus of MYC and a DNA-binding domain at the carboxy-terminus, but the central portion between these domains has not been studied in detail. To rectify this deficit, we recently initiated screens to identify proteins that bind to the central portion of MYC, with the idea that these proteins would reveal new aspects of MYC regulation or function; some of which may expose new ways to target MYC activity. One novel MYC-interaction partner to emerge from this screen was WDR5.

WDR5 is a chromatin-associated protein that co-binds with MYC at a majority of its target genes. MYC binds weakly to WDR5 by engaging a structured hydrophobic cleft on one side of the WDR5 protein. Mutations in MYC that disrupt interaction with WDR5 block the ability of MYC to bind chromatin and disable its tumorigenic properties in mice, demonstrating that WDR5 is a critical co-factor for MYC. These studies led to a revised model for target gene recognition by MYC in which WDR5 facilitates the recruitment of MYC/MAX complexes to chromatin, and revealed that the MYC–WDR5 interface is a tractable surface for small molecule inhibition. In collaboration with the laboratory of Dr. Stephen Fesik we seek to discover and validate drug-like molecules that disrupt the MYC–WDR5 interaction and explore their utility in cell and animal-based models of cancer.

Citation Format: William Tansey. Novel approaches for targeting MYC. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Targeting the Vulnerabilities of Cancer; May 16-19, 2016; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(1_Suppl):Abstract nr IA15.