Omomyc is an investigational therapeutic mini-protein under study as a potential treatment for various cancers. It is being developed as a first-in-modality direct inhibitor, aiming to address targets previously considered inaccessible by traditional drug development methods.
Targeting the Myc Oncogene
Cancer cells often exhibit unchecked growth and division, frequently driven by oncogenes. These genes, when mutated or overexpressed, promote tumor development. The Myc protein is a regulator of cellular programs, orchestrating processes like cell growth, metabolism, and proliferation. While Myc is involved in normal cell functions, its deregulation is observed in approximately 70% of human cancers, contributing to aggressive disease and resistance to existing therapies.
For decades, the Myc protein has been considered “undruggable.” This challenge stems from its intrinsically disordered protein structure, lacking a fixed shape or well-defined pockets for conventional drugs. Additionally, Myc’s primary function occurs within the cell nucleus, posing a significant hurdle for drug delivery. These structural and localization complexities made it difficult to design compounds that could specifically inhibit Myc’s activity without causing widespread side effects in healthy cells, where Myc also plays a role.
Mechanism of Action
Omomyc functions as a “dominant negative” inhibitor of Myc, interfering with its normal activity by mimicking a part of the protein. This mini-protein is a modified version of human c-Myc. It contains specific alterations that enable it to disrupt the formation of functional complexes involving Myc.
Normally, Myc needs to partner with another protein called MAX to form a heterodimer. This Myc/MAX complex then binds to specific DNA sequences, known as E-boxes, to activate genes that drive cell proliferation and survival. Omomyc intervenes by binding to Myc, preventing it from forming these functional heterodimers with MAX.
Omomyc can also form homodimers with itself or heterodimers with MAX. These alternative complexes bind to the same E-box DNA sequences, but unlike the active Myc/MAX complex, they are transcriptionally inactive. By occupying these sites, Omomyc acts like a “dummy key” that fits into the lock but cannot turn it, blocking the correct key from activating the gene. This mechanism shuts down the uncontrolled cell growth and survival pathways that are hallmarks of cancer cells.
Clinical Development and Applications
The clinical derivative of Omomyc, known as OMO-103, has progressed in clinical trials. It completed a first-in-human Phase I dose-escalation study involving patients with various advanced solid tumors. These included individuals with pancreatic, bowel, and non-small cell lung cancers, who had previously undergone multiple lines of treatment.
The Phase I trial demonstrated that OMO-103 was safe and well-tolerated. Most observed side effects were mild, classified as Grade 1, and included common infusion-related reactions such as chills, fever, nausea, rash, and low blood pressure. Only one patient experienced a dose-limiting toxicity, which was inflammation of the pancreas.
Preliminary results from the trial showed signs of clinical activity, with some patients experiencing stabilization of their disease. For example, one patient with pancreatic cancer remained on the study for over six months, showing an eight percent tumor shrinkage and a substantial reduction in tumor-derived DNA circulating in the bloodstream. The study confirmed that OMO-103 engaged its target, effectively blocking Myc’s transcriptional activity within tumors.
The Future of Myc Inhibitors
The development of Omomyc represents a scientific achievement, serving as a “proof-of-concept” that historically “undruggable” targets like Myc can be inhibited. This challenges the long-held belief that Myc’s disordered structure made it inaccessible to direct therapeutic intervention. Omomyc’s success, particularly its ability to directly inhibit Myc with an acceptable safety profile, inspires confidence in pursuing similar mini-protein therapeutics.
This advancement opens new avenues for drug development, not only for Myc but also for other challenging protein targets implicated in cancer and various diseases. It paves the way for a new class of precision anti-cancer drugs designed to target previously elusive drivers of tumor growth. The ongoing research and clinical progress with Omomyc offer promise for patients with Myc-driven cancers and the broader field of oncology.