Provided are methods and compositions for identifying inhibitors of an interaction between the oncogenic transcription factor MYC and its cofactor TRRAP. The methods involve both cell-based and in vitro approaches for probing an interaction between MYC and TRRAP and for identifying inhibitors of a MYC-TRRAP interaction. Also provided are compounds for use as inhibitors of an interaction between MYC and TRRAP, and methods for developing a cancer therapeutic from such compounds, including methods for derivatizing such inhibitors and for testing the inhibitors and derivatized inhibitors for an ability to treat cancer in a subject. The methods, compounds, and compositions provided herein can provide various advantages, such as a means to target the oncogenic transcription factor MYC in cancer.