Cell-Permeable Miniproteins to target Myc oncoprotein

Chemically engineered family of Max-derived transcription factor (TF) analogs (μMax modulators) with intrinsic cell permeability, nanomolar DNA binding, and enhanced stability. These abiotic proteins can directly modulate gene expression driven by Myc TF – offering a therapeutic strategy for drugging the undruggable Myc pathway.

Unmet Need

TFs, especially Myc, are among the most critical yet undruggable targets in oncology. Native proteins cannot enter cells efficiently, degrade quickly, and lack tunability – limiting their therapeutic potential. There is a significant need for stable, cell-permeable protein modulators that can directly manipulate transcription inside cells.

Our Solution

We engineered synthetic μMax modulators using total chemical synthesis, sequence optimization, and aromatic staples.

The result: μMax20 analogs, a fully synthetic, cell-penetrating TFs with potent E-box binding affinity and specificity, and markedly improved stability. μMax20 analogs enter cells without delivery vehicles and effectively modulate Myc-dependent transcription.

Unique Advantages

• Intrinsic cell permeability (no CPPs or viral-based delivery)
• Nanomolar, sequence-specific DNA binding
• 2-3x improved proteolytic stability
• Fully synthetic, modular, and rapidly tuneable
• Direct manipulation of Myc-driven transcription

Competitive Advantages

• Effective therapeutic proteins for targeting Myc – a space unmet by small molecules
• Chemical modifications not achievable by biological expression
• Rapid design cycle enables multiple analogs and optimization paths
• Outperforms native TFs in delivery, potency, and stability
• Outperforms the dominant Myc inhibitor, the Omomyc drug candidate

Potential Applications

• Therapeutics- Oncology: Myc-driven cancers (lymphoma, colon, ovarian, lung)
• Drug discovery tools: probing TF-DNA interactions
• Regenerative medicine: transient gene expression control

2S_p-μMax20 and 2S_b-μMax20 are intrinsically cell-permeable inhibitors of Myc-driven oncogenic transcription. A) Cell permeability and nuclear localization at 250 nM. B) 2S_p-μMax20 and 2S_b-μMax20 supress Myc-dependant gene transcription. The drug candidate, Omomyc, serves as a positive control. C) 2S_p-μMax20 and 2S_b-μMax20 markedly inhibit cancerous HeLa cell proliferation.

References

Harel et al., Chemical Engineering of Transcription Factors Uncovered Cell-Permeable μMax Modulators, J. Am. Chem. Soc, 2025, 147, 46, 42647-42658.