The transcription factor family consists of c-MYC, L-MYC and N-MYC, which are the main regulators of cellular processes such as cell proliferation, cell differentiation, cell cycle and metabolism. But when these proteins become overactive, they speed up these processes, leading to tumorigenesis. Thus, MYC is one of the most commonly dysregulated proteins in cancer. However, MYC has long been considered “difficult to drug”.
Because it has no structurally defined binding pocket and acts through protein-protein interactions, it offers fewer opportunities for active drugs. In addition, MYC also plays a role in the nucleus, regulating a series of signaling pathways, and blocking it may cause many toxicity problems.
However, through people’s unremitting efforts, some cell-penetrating peptides or small molecule inhibitors or degradation agents targeting MYC have been developed and entered the clinical stage. A cell-penetrating peptide called OMO-103 was shown to be safe and potentially effective in preliminary human trials at the EORTC-NCI-AACR meeting in Barcelona. In a small phase I trial in heavily pretreated patients with solid cancers, treatment was well tolerated, with eight participants in stable disease. In addition, more drugs targeting MYC are also emerging, and the dawn of the journey to conquer MYC is emerging.
The development of OMO-103 stems from the analysis of the structure of MYC and its main protein partner MAX, both of which contain closely related dimerization domains. But, strangely, MYC can only bind MAX, but MAX can bind many other proteins, including itself. After comparing the structures of MYC and MAX, the researchers identified four charged amino acids that likely prevent MYC homodimerization. When these repelling amino acids were exchanged for neutral amino acids, the resulting engineered peptide Omomyc could bind endogenous MYC.
MYC–MAX dimers normally bind to DNA to regulate protein expression, whereas Omomyc binds to MYC to dissociate the native transcription factor from its bound DNA. Simultaneous binding of Omomyc–Omomyc and Omomyc–MAX dimers to DNA without altering transcription blocks the function of bona fide MYC–MAX dimers. Experiments with the Omomyc transgene showed that MYC inhibition is safe and can eradicate lung cancer in mice.
Peptomyc initiated a Phase 1 trial of OMO-103, a new version of Omomyc, in April 2021. The results of this trial, which enrolled 22 heavily pretreated patients with solid tumors, provide further evidence that MYC inhibition is safe and potentially effective as an anticancer strategy. The most common treatment-emergent adverse events were infusion-related reactions, back pain, anemia, and fatigue. In terms of efficacy, there was no complete or partial response to OMO-103, but 8 patients were in stable condition, and 2 patients with pancreatic cancer received OMO-103 as fourth-line therapy. Currently, Peptomyc is planning for its next clinical trial, prioritizing OMO-103 in combination with chemotherapy in pancreatic cancer.
At present, in addition to OMO-103, studies on some other MYC targeting molecules are emerging and may provide better pharmacological properties. For example, researchers at the University of Chicago just reported in the journal Nature Biotechnology that a short peptide that mimics the dimerization domain of MAX could be used to inhibit MYC in cells.
Direct-acting small molecules are also under investigation, for example, a small molecule inhibitor called MYCi975 can disrupt the MYC–MAX dimer, promote MYC degradation and kill cancer cells. Phase 1 trials of the drug could begin by 2024.
In addition, PROTAC-targeted degraders that bind and disrupt MYC are also on the horizon. Kintor Pharmaceuticals will present preclinical results of its dual c-MYC and GSPT1 glue degraders at an upcoming American Society of Hematology meeting. A UC Berkeley team has just shown on BioRxiv how the E3 ligase UBR5 degrades MYC and other transcription factors, offering a possible alternative route for MYC-targeting degraders.
Omega Therapeutics is developing an mRNA-based approach to inhibit the expression of MYC by modifying the genome structure. The company started a phase I trial of its MYC-targeting drug OTX-2002 in October this year.
Monte Rosa Therapeutics’ GSPT1 degrader MRT-2359 was also presented at the EORTC-NCI-AACR conference. Monte Rosa began research on MYC-targeted degradation drugs early on, by screening its degradation in cell lines that MYC can be turned on and off substances, they identified compounds that control MYC activity. GSPT1 degradants were subsequently screened in more than 500 cancer cell lines and 80 disease xenograft models, demonstrating their anticancer potential. A Phase I trial of MRT-2359 is currently ongoing in MYC-driven tumors. Additionally, BMS is testing a GSPT1 degrader called CC-90009 in a phase I/II trial in acute myeloid leukemia.
1. Climbing cancer’s MYC mountain. Nat Rev Drug Discov． 2022 Nov 11．
2. Little medicine