Demystifying the Druggability of the MYC Family of Oncogenes

Abstract

The MYC family of oncogenes (MYC, MYCN, and MYCL) encodes a basic helix−loop−helix leucine zipper (bHLHLZ) transcriptional regulator that is responsible for moving the cell through the restriction point. Through the HLHZIP domain, MYC heterodimerizes with the bHLHLZ protein MAX, which enables this MYC-MAX complex to bind to E-box regulatory DNA elements thereby controlling transcription of a large group of genes and their proteins. Translationally, MYC is one of the foremost oncogenic targets, and deregulation of expression of the MYC family gene/proteins occurs in over half of all human tumors and is recognized as a hallmark of cancer initiation and maintenance. Additionally, unexpected roles for this oncoprotein have been found in cancers that nominally have a non-MYC etiology. Although MYC is rarely mutated, its gain of function in cancer results from overexpression or from amplification. Moreover, MYC is a pleiotropic transcription factor possessing broad pathogenic prominence making it a coveted cancer target. A widely held notion within the biomedical research community is that the reliable modulation of MYC represents a tremendous therapeutic opportunity given its role in directly potentiating oncogenesis. However, the MYC-MAX heterodimer interaction contains a large surface area with a lack of well-defined binding sites creating the perception that targeting of MYC-MAX is forbidding. Here, we discuss the biochemistry behind MYC and MYC-MAX as it relates to cancer progression associated with these transcription factors. We also discuss the notion that MYC should no longer be regarded as undruggable, providing examples that a therapeutic window is achievable despite global MYC inhibition.

Analyses of Genes Critical to Tumor Survival Reveal Potential ‘Supertargets’: Focus on Transcription

“…For example, the small molecule inhibitor AI-10-49 selectively disrupted the interaction between the aberrant activator CBF-β and DNA binding transcriptional factor RUNX1, thereby restoring normal expression patterns and delaying leukemia progression in mice [67]. Another example of a protein-protein interaction inhibitor is the small molecules that disrupt MDM2-p53 binding to reduce p53 ubiquitination, thereby increasing p53 abundance and cell death [68][69][70]. A series of PROTAC (PROteolysis Targeting Chimera)-based drugs targeting transcription factors have entered clinical trials [71][72][73].…”

Synthetic Peptides: Promising Modalities for the Targeting of Disease‐Related Nucleic Acids

“…The c-Myc TF plays a role in a multitude of cellular processes such as cell proliferation and survival, differentiation, apoptosis, metabolism and DNA repair. [45] It belongs to the basic helix-loop-helix leucine zipper (bHLHLZ) family of TFs. The full length protein consists of an N-terminal transactivation domain followed by a central domain with a nuclear localization signal and the C-terminal bHLHLZ domain.…”

“…This enables the Myc/Max heterodimer to bind to a DNA sequence called enhancer box (E-box) with the canonical sequence CACGTG (Figure 2a, left). [45] Activation of gene transcription is achieved by recruitment of different cofactors such as histone acetyltransferase complexes (TTRAP, GCN5, TIP60, TIP48) eventually leading to histone acetylation and allowing RNA polymerase II binding. [32,[46][47][48] Acting within the Myc/Max/Mxd network, Myc can only heterodimerize with Max whereas Max itself can homodimerize as well as heterodimerize with other bHLHLZ proteins in the network, such as Mxd1-4 and others.…”

“…The c‐Myc TF plays a role in a multitude of cellular processes such as cell proliferation and survival, differentiation, apoptosis, metabolism and DNA repair [45] . It belongs to the basic helix‐loop‐helix leucine zipper (bHLHLZ) family of TFs.…”

“…While monomeric Myc is unable to bind to DNA, it heterodimerizes with its partner Myc‐associated protein X (Max) through coiling of their zipper domains. This enables the Myc/Max heterodimer to bind to a DNA sequence called enhancer box (E‐box) with the canonical sequence CACGTG (Figure 2a, left) [45] . Activation of gene transcription is achieved by recruitment of different cofactors such as histone acetyltransferase complexes (TTRAP, GCN5, TIP60, TIP48) eventually leading to histone acetylation and allowing RNA polymerase II binding [32,46–48] …”