A bivalent lysine-acetylated small-molecule binding site in MYC

Dikshat Gopal Gupta; Mihai Ioan Truica; Jin‐gon Shim; J. Brandon Parker; Mahil Lambert; Adam W. T. Steffeck; Daniel Herald Ryan; Hao Pan; Kerem Kahraman; Xinyan Lu; William Yang; Kenji Unno; Ala A. Elmashae; Megan M. Kerber; Caitlyn Elysse Brookins; Huiying Han; Mary F. Dufficy; Songhua Quan; Debabrata Chakravarti; Gary E. Schiltz; Joshua J. Ziarek; Sarki Abba Abdulkadir

doi:10.64898/2026.03.02.707789

Cancer BiologybioRxivAug 18, 2026

Preprint

A bivalent lysine-acetylated small-molecule binding site in MYC

Dikshat Gopal Gupta iD, Mihai Ioan Truica iD, Jin‐gon Shim iD, J. Brandon Parker iD, Mahil Lambert iD, Adam W. T. Steffeck iD, Daniel Herald Ryan iD, Hao Pan iD, Kerem Kahraman iD, Xinyan Lu iD, William Yang iD, Kenji Unno iD, Ala A. Elmashae iD, Megan M. Kerber iD, Caitlyn Elysse Brookins iD, Huiying Han, Mary F. Dufficy iD, Songhua Quan iD, Debabrata Chakravarti iD, Gary E. Schiltz iD, Joshua J. Ziarek iD, Sarki Abba Abdulkadir iD

Abstract

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.

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