Targeting c-Myc and a Molecular Glue: UB025

The transcription factor c-Myc has emerged as a critical target in oncology, given its aberrant expression in more than 70% of human cancers. Preclinical studies have demonstrated that direct inhibition of c-Myc can lead to rapid tumor regression in mouse models, with remarkably mild and reversible side effects. This compelling evidence suggests that targeting c-Myc could be a groundbreaking therapeutic strategy in cancer treatment. However, despite its potential, developing effective inhibitors for c-Myc has proven to be a significant challenge in drug discovery and development. The complexities surrounding c-Myc inhibition present both an obstacle and an opportunity for innovative pharmaceutical companies looking to make a substantial impact in cancer therapy.

Understanding c-Myc

c-Myc belongs to the basic-helix-loop-helix-leucine zipper (bHLHZip) family, and it plays a crucial role in regulating cell growth, differentiation, metabolism, and death. Its significance is further underscored by its frequent dysregulation in numerous human cancers, making it a prime target for pharmaceutical intervention. c-Myc is the prototype of the Myc family, which also includes N-Myc and L-Myc in mammalian cells. While these proteins share high homology, their distribution patterns differ significantly. c-Myc is ubiquitous and abundant in proliferating cells, whereas N-Myc and L-Myc exhibit more restricted expression during specific stages of cell and tissue development.

The functionality of c-Myc hinges on its ability to heterodimerize with another protein called Max. This process, governed by the coiling of their bHLHZip domains, is essential for c-Myc to fold correctly and become transcriptionally active. Once formed, the c-Myc/Max complex acts as a master transcriptional regulator by binding to a specific DNA consensus sequence known as the Enhancer-box (E-box), represented by CANNTG.

Crystal structure of the c-Myc/Max dimer bound to E-box DNA (PDB ID 1NKP). Madden, S. K., de Araujo, A. D., Gerhardt, M., Fairlie, D. P. & Mason, J. M. Taking the Myc out of cancer: toward therapeutic strategies to directly inhibit c-Myc. Mol Cancer 20, 3 (2021).

The binding of the c-Myc/Max dimer to E-box DNA initiates a cascade of events that ultimately leads to gene transcription. This process involves the recruitment of various proteins and complexes, including the transformation/transcription domain-associated protein (TRRAP), histone acetytransferase complexes TIPS60 and GCN5, p300/CBP-associated factor, and ATP-binding protein TIP48. These recruitments result in the acetylation of histones H3 and H4, opening the chromatin structure and allowing RNA polymerase II machinery to access the core promoter.

c-Myc's influence on cellular processes is vast, targeting up to 15% of all genes. Its reach extends to cell cycle regulation (through cyclins D1, D2, B1, and cyclin-dependent kinase 4), metabolism (via enolase A, hexokinase II, lactate dehydrogenase A, phosphofructokinase, and glucose transporter I), protein synthesis, ribosome biogenesis, and cell adhesion. Interestingly, c-Myc can also repress transcription, although this aspect is less well-understood than its activating capabilities.

c-Myc and Cancer

While tightly controlled in normal cells, c-Myc becomes a rogue agent in most human cancers, earning its reputation as one of the most significant human oncogenes. This transformation doesn't typically result from direct mutations to c-Myc itself, but rather through a variety of mechanisms at the DNA, RNA, and protein levels that lead to its overexpression.

When c-Myc levels surge beyond their normal boundaries, c-Myc starts interacting with lower affinity E-boxes - specific DNA sequences that it normally wouldn't engage with at physiological concentrations. This expanded reach triggers changes in gene activation, particularly those governing cell proliferation and growth, setting the stage for tumorigenesis. Moreover, previously silent genes - the nontarget genes - may also be activated.

Wang, C. et al. Alternative approaches to target Myc for cancer treatment. Sig Transduct Target Ther 6, 1–14 (2021).

Challenges in Targeting c-Myc

Despite its prominent role in cancer development, c-Myc has proven to be an elusive target for drug developers. For decades, researchers have pursued inhibitors for this oncogenic protein, but progress has been frustratingly slow. Two major hurdles stand in the way of directly targeting the c-Myc oncoprotein:

First, c-Myc's molecular structure presents a significant challenge. As an Intrinsically Disordered Protein (IDP), c-Myc lacks the well-defined, stable structure that typically makes proteins amenable to drug targeting. Its extended unstructured surface, particularly in the unbound bHLHZip domain, is devoid of the "hotspots" and deep hydrophobic pockets that conventional small molecule drugs usually latch onto. Adding to this difficulty, c-Myc doesn't possess any catalytic activity, ruling out the possibility of using low molecular weight enzyme inhibitors to block its function.

The second major obstacle is c-Myc's location within the cell. Endogenous c-Myc resides in the nucleus, a cellular compartment that's notoriously difficult for many therapeutic agents to access. Any potential drug must not only penetrate the cell membrane but also efficiently translocate to the nucleus. This requirement effectively eliminates antibody-based agents, which are typically too large to enter the nucleus.

Given these challenges, researchers have had to think creatively about how to target Myc-dependent neoplasms. Current approaches to treating Myc-deregulated cancers generally fall into five categories:

• Targeting MYC transcription

• Targeting MYC mRNA translation

• Targeting Myc stability

• Targeting Myc–Max interaction

• Targeting accessibility of Myc to downstream genes

Each of these strategies aims to disrupt the Myc-driven oncogenic process at different points, from its production to its interactions with other cellular components. While these approaches show promise, they also underscore the complexity of targeting such a fundamental cellular player.

UB025

At Unibest, we present a first-in-class small molecular glue, UB025, targeting c-Myc open for NewCo.

• UB025 is an orally potent small molecular glue targeting c-Myc for CHIP E3 ligase-mediated degradation

• Potential breakthrough therapy designation: UB025 could eradicate c-Myc⁺ acute myeloid leukemia(AML), multiple myeloma(MM) and lymphoma, and regress lethal pancreatic, brain, prostate, lung, and gastric cancers in mouse models.

• Wide synergistic effect: UB025 shows significant synergistic effects with various drugs such as K-RAS and Bcl-2 inhibitors.

• Good DMPK: UB025 is stable at room temperature for 3 years and reachs oral bioavailability >70% in rat and dog.

• Safety management: Low treatment-related AEs (TRAEs) at efficacy dose. UB025's toxic targets are c-Myc expressing organs and tissues, mainly including bone marrow and reproductive system. The toxicity is tolerable and reversible, and can be solved by optimizing therapy regimen based on the differential expression of c-Myc between cancer and normal cells.

• Intellectual property: UB025's PCT patent has been authorized worldwide.

• Wide indications: > 70% of hematological tumor (leukemia、lymphoma, multiple myeloma) and >50% of solid tumors are positive for c-Myc.

If you are interested for explore this assest for the NewCo opportunity, contact bd@unibestcn.com or make a reservation following this link.

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