The long journey to bring a Myc inhibitor to the clinic

Abstract

The oncogene Myc is deregulated in the majority of human tumors and drives numerous hallmarks of cancer. Despite its indisputable role in cancer development and maintenance, Myc is still undrugged. Developing a clinical inhibitor for Myc has been particularly challenging owing to its intrinsically disordered nature and lack of a binding pocket, coupled with concerns regarding potentially deleterious side effects in normal proliferating tissues. However, major breakthroughs in the development of Myc inhibitors have arisen in the last couple of years. Notably, the direct Myc inhibitor that we developed has just entered clinical trials. Celebrating this milestone, with this Perspective, we pay homage to the different strategies developed so far against Myc and all of the researchers focused on developing treatments for a target long deemed undruggable.

Activation of the Integrated Stress Response overcomes multidrug resistance in FBXW7-deficient cells

“…Finally, MYC overexpression renders cancer cells sensitive to targeting mitochondrial activity with antibiotics 69 or drugs targeting OXPHOS 70 . Given the increasing availability of chemical- or peptide-based therapies for targeting MYC 71 , whether these agents might be useful as a general strategy to overcome the MDR in cancer emerges as an interesting possibility.…”

Targeting key proteins involved in transcriptional regulation for cancer therapy: Current strategies and future prospective

“…The above reasons have resulted in the authentication of inhibitors primarily via high‐throughput screening (HTS) of chemical libraries rather than traditional structure‐based design 184 . Yet so far, due to insufficient druggability probably, no small‐molecule inhibitors of c‐Myc/Max PPI have been tested in clinical trials 185–187 . Several small molecules such as Kj‐Pyr‐9, MYCMI‐6, MYCi361 and MYCi975 with potent anticancer activities in vivo are expected to be further developed into potential preclinical drug candidates (Figure 5).…”

“…184 Yet so far, due to insufficient druggability probably, no small-molecule inhibitors of c-Myc/Max PPI have been tested in clinical trials. [185][186][187] Several small molecules such as Kj-Pyr-9, MYCMI-6, MYCi361 and MYCi975 with potent anticancer activities in vivo are expected to be further developed into potential preclinical drug candidates (Figure 5). 183,[188][189][190] Some of TFs require stable PPIs as a homodimer to exert transcriptional activities.…”

“…253,254,267 Through large-scale genetic screening, several MYC-dependent vulnerable repertoires have been verified as synthetic lethal partners in MYC-associated cancers (Figure 10B), including proteins that regulate MYC expression (BRD4, CDK9, and CDK7), MYC function, and stability (AURKA/B, PLK1, Pim-1, MAX, and MIZ1), MYC-driven proliferation and apoptosis (CDK1, CHK1, TPX2 DNA-PK, ATR, and MCL1) and MYC-driven cellular metabolism (IMPDH2, mTOR, UHL, BUD31, and ARK5). 187,268 RNAi screening has inspired the identification of several unconventional synthetic lethal partners of MYC, including SAE1/2, CK1ε, and PES1. 269,270 CRISPR genetic screening provides another approach for discovering novel synthetic lethal targets of MYC, thereby the RNA transporter XPO1 was identified via genome-wide CRISPR screens.…”

Oxidative stress potentiates the therapeutic action of a mitochondrial complex I inhibitor in MYC-driven B-cell lymphoma

“…Besides multiple attempts to target MYC directly 8,9 , much effort in the field was aimed at the identification of synthetic-lethal interactions as means to develop targeted therapies against MYC-associated tumors 7,10 . Among these, we and others identified pharmacological inhibition of the mitochondrial ribosome with the antibiotic tigecycline as a therapeutically viable strategy against MYC-driven lymphoma [11][12][13] .…”