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Discovery of a Covalent Ligand Targeting an Intrinsically Disordered Cysteine Within MYC

Boike, Lydia, Cioffi, Alexander, Majewski, Felix C., Co, Jennifer, Henning, Nathaniel J., Jones, Michael, Liu, Gang, McKenna, Jeffrey, Tallarico, John, Schirle, Markus and Nomura, Daniel K. (2020) Discovery of a Covalent Ligand Targeting an Intrinsically Disordered Cysteine Within MYC. Cell chemical biology. ISSN 2451-9448


MYC is a major oncogenic transcriptional driver of most human cancers. Yet, MYC has remained intractable to direct targeting because much of MYC is intrinsically disordered and there are no known obvious pockets within MYC that can be pharmacologically interrogated. Here, we have performed a cysteine-reactive covalent ligand screen to identify compounds that could disrupt the binding of MYC to its DNA consensus sequence in vitro and also impair MYC transcriptional activity in situ in cells. We have identified a covalent ligand hit EN4 that uniquely and covalently targets cysteine 171 (C171) of MYC within a predicted intrinsically disordered region of the protein. We show EN4 treatment directly targets MYC in cells and inhibits MYC transcriptional activity, downregulates multiple MYC transcriptional targets, and impairs breast tumor xenograft growth in vivo. We further show that mutation of C171 to a tyrosine attenuates the MYC inhibitory activity of EN4 in cells. We also show initial structure-activity relationships of EN4 and identify compounds that show improved potency. Overall, we identify a novel ligandable site within an intrinsically disordered region of MYC that leads to inhibition of MYC transcriptional activity.

Item Type: Article
Date Deposited: 13 Oct 2020 00:45
Last Modified: 13 Oct 2020 00:45


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