Targeting the function of MYC oncoproteins holds the promise of achieving conceptually new and effective anticancer therapies that can be applied to a broad range of tumors. The nature of the target however—a broadly, possibly universally acting transcription factor that has no enzymatic activity and is largely unstructured unless complexed with partner proteins—has so far defied the development of clinically applicable MYC-directed therapies. At the same time, lingering questions about exactly which functions of MYC proteins account for their pervasive oncogenic role in human tumors and need to be targeted have prevented the development of effective therapies using surrogate targets that act in critical MYC-dependent pathways. In this review, we therefore argue that rigorous testing of critical oncogenic functions and protein/protein interactions and new chemical approaches to target them are necessary to successfully eradicate MYC-driven tumors.

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