10058-F4: Unraveling c-Myc/Max Disruption in Cancer and Telomerase Regulation

Introduction: The Expanding Frontier of c-Myc Inhibition

Targeting the c-Myc transcription factor remains a central strategy in cancer research due to its pivotal role in cell proliferation, metabolism, and survival. The small-molecule c-Myc-Max dimerization inhibitor 10058-F4 (SKU: A1169) has emerged as a powerful, cell-permeable tool for dissecting oncogenic pathways and modulating apoptosis. While existing literature has thoroughly characterized 10058-F4’s canonical action in apoptosis assays and cancer biology, this article offers a distinct perspective: we synthesize recent advances in c-Myc/Max disruption, highlight the compound’s nuanced impact on telomerase regulation and DNA repair, and outline its implications for future cancer therapies.

Mechanism of Action: Disruption of the c-Myc/Max Heterodimer

The c-Myc/Max Axis in Oncogenesis

c-Myc is a transcription factor that orchestrates the expression of genes critical for cell cycle progression and metabolism. Its oncogenic activity is contingent upon heterodimerization with Max, enabling DNA binding at E-box sequences and activation of pro-proliferative genes. Dysregulation of this axis is a hallmark of diverse malignancies, including acute myeloid leukemia (AML) and prostate cancer.

10058-F4: A Selective Small-Molecule c-Myc Inhibitor

10058-F4, chemically designated as (5E)-5-[(4-ethylphenyl)methylidene]-2-sulfanylidene-1,3-thiazolidin-4-one, operates by selectively disrupting c-Myc-Max dimerization. This disruption impedes c-Myc binding to target DNA sequences, thereby suppressing c-Myc-driven transcriptional programs. The consequence is a rapid downregulation of c-Myc mRNA and protein levels, triggering cell cycle arrest and apoptosis via the mitochondrial pathway. Notably, 10058-F4’s cell-permeable properties facilitate robust intracellular delivery, making it a preferred c-Myc/Max heterodimer disruption pathway probe for both in vitro and in vivo studies.

Downstream Effects: Mitochondrial Apoptosis and Bcl-2 Modulation

By blocking c-Myc/Max activity, 10058-F4 activates the mitochondrial apoptosis pathway. This involves modulation of Bcl-2 family proteins, increased cytochrome C release, and subsequent activation of caspases. In AML cell lines (e.g., HL-60, U937, NB-4), 10058-F4 induces apoptosis in a dose- and time-dependent manner, with pronounced effects at 100 μM after 72 hours. In vivo, intravenous administration in SCID mice bearing DU145 and PC-3 human prostate cancer xenografts results in tumor growth inhibition, albeit with variable efficacy—highlighting the complexity of c-Myc-driven tumor biology.

Comparative Analysis: 10058-F4 Versus Alternative c-Myc Inhibition Strategies

While earlier reviews such as "10058-F4: A Next-Generation c-Myc-Max Dimerization Inhibitor" have focused on the compound’s primary mechanism and its role in apoptosis assay development, our analysis delves deeper into the molecular interplay between c-Myc/Max inhibition and telomerase regulation—a frontier less explored in current content.

Alternative approaches to c-Myc inhibition, such as antisense oligonucleotides, dominant-negative peptides, and indirect inhibition via upstream signaling pathways, often suffer from poor cell permeability, off-target effects, and limited in vivo applicability. In contrast, 10058-F4’s small-molecule structure ensures high bioavailability and specificity, making it a versatile tool for both mechanistic research and preclinical modeling.

Beyond Apoptosis: 10058-F4 as a Probe for Telomerase and DNA Repair Pathways

Linking c-Myc Regulation to Telomerase Expression

Recent revelations have illuminated the intricate relationship between c-Myc activity and telomerase reverse transcriptase (TERT) expression. c-Myc directly regulates the TERT promoter, thereby influencing telomerase activity—a critical determinant of cellular immortality in stem cells and cancer. However, the regulatory network is more complex than direct transcriptional control.

APEX2-Mediated DNA Repair and Its Synergy with c-Myc Inhibition

A groundbreaking study (Stern et al., 2024) has uncovered a novel role for the DNA repair enzyme APEX2 in promoting efficient TERT expression in human embryonic stem cells and melanoma. APEX2, but not its paralog APEX1, is essential for sustaining telomerase activity, with knockdown experiments revealing reduced TERT mRNA and telomerase function. Chromatin immunoprecipitation identified significant APEX2 binding near mammalian-wide interspersed repeats (MIRs) within TERT intron 2, suggesting that DNA repair at repetitive elements modulates TERT transcriptional output.

By integrating 10058-F4 into this paradigm, researchers can probe how c-Myc/Max disruption interacts with APEX2-dependent repair pathways to influence telomerase regulation and genomic stability. This dual targeting opens new avenues for exploring synthetic lethality and vulnerabilities in cancer cells reliant on both c-Myc and telomerase activity.

Advanced Applications: Acute Myeloid Leukemia and Prostate Cancer Xenograft Models

Acute Myeloid Leukemia Research

10058-F4 stands out as a cell-permeable c-Myc inhibitor for apoptosis research in hematologic malignancies. In AML cell lines, it induces mitochondrial apoptosis with clear dose-responsiveness, enabling precise dissection of c-Myc-dependent survival pathways. This complements, but expands upon, prior analyses such as "10058-F4: Novel Insights into c-Myc Inhibition and Mitochondrial Apoptosis", by connecting these apoptotic effects to broader DNA repair and telomerase regulatory contexts.

Prostate Cancer Xenograft Models

In vivo efficacy of 10058-F4 has been validated in SCID mice xenografted with DU145 and PC-3 human prostate cancer cells. Intravenous administration results in suppressed tumor growth, though inter-tumor heterogeneity affects response magnitude. This model system is invaluable for preclinical validation of c-Myc/Max heterodimer disruption pathway inhibitors and for characterizing the interplay between c-Myc, mitochondrial apoptosis, and telomerase regulation in solid tumors.

Technical Considerations: Solubility, Storage, and Experimental Design

10058-F4 is supplied as a solid, with a molecular weight of 249.35. Its solubility profile is optimal for laboratory workflows: ≥24.9 mg/mL in DMSO and ≥2.64 mg/mL in ethanol, but insoluble in water. For experimental integrity, solutions should be prepared fresh and used promptly; long-term storage of solutions is not recommended. The compound should be stored at -20°C to maintain stability.

Integrating 10058-F4 into Next-Generation Oncogenic Pathway Research

While comprehensive reviews such as "10058-F4: Advanced Applications of a c-Myc-Max Dimerization Inhibitor" catalog the compound’s established uses in apoptosis and cancer biology, our current analysis uniquely synthesizes recent advances in telomerase regulation and DNA repair, laying the groundwork for innovative research directions. Specifically, leveraging 10058-F4 in combination with genetic or pharmacologic APEX2 modulation may reveal synergistic anti-cancer strategies and new therapeutic windows.

Conclusion and Future Outlook

10058-F4 continues to be at the forefront of small-molecule c-Myc-Max dimerization inhibitors for cancer research. Its unique ability to disrupt c-Myc/Max heterodimerization, induce mitochondrial apoptosis, and serve as a probe for telomerase and DNA repair pathways positions it as a cornerstone asset for both basic and translational oncology. The emerging intersection between c-Myc inhibition, APEX2-mediated DNA repair, and TERT expression—as highlighted in Stern et al., 2024—offers a fertile ground for discovery, particularly in the context of acute myeloid leukemia research and prostate cancer xenograft models.

By integrating the mechanistic insights and advanced applications discussed here, researchers are poised to unlock new therapeutic possibilities and deepen our understanding of cancer cell vulnerabilities. For detailed product information and ordering, visit the 10058-F4 product page.