A bivalent lysine-acetylated small-molecule binding site in MYC
MYC is an important, yet challenging target in oncology as it lacks traditional druggable pockets. Here, we show that two regions of MYC, the basic-helix-loop-helix (bHLH) domain, and extended MYC Box II (eMBII) come together to form a bivalent, high-affinity small-molecule MYC inhibitor (MYCi) binding site. CRISPR-tiling mutagenesis identified mutations in the vicinity of the eMBII and bHLH regions that together confer MYCi resistance. Importantly, acetylation of K148 in eMBII, which is essential for MYC oncogenicity in vivo, enhanced MYCi binding affinity and is predicted to increase the structural order of this region. Furthermore, MYCi selectively modulated the expression of the same genes regulated by lysine-acetylated MYC in cancer cells. These studies provide a rationale for selective targeting of acetylated, oncogenic MYC with small molecules.