UNC7938

Novel destabilizer of the endosome membrane, enhancing the endosome-leakage activity of cell-penetrating peptides and facilitating the endosomal escape of macromolecules initially internalized by mammalian cells via endocytosis

What is UNC7938?

• UNC7938 (also known by UNC-10217938A) is a small molecule identified from high-throughput screening of the “UNC compounds” library. OUP Academic+2aobious.com+2

• It is described as an “oligonucleotide enhancing compound” (OEC), i.e. a molecule that helps antisense oligonucleotides (ASOs) or similar nucleic acid therapeutics overcome intracellular delivery barriers. PMC+2OUP Academic+2

• Chemically, its structure includes aromatic and amine moieties; some analog studies have modified parts (e.g. the carbamate group) to optimize activity and toxicity. ResearchGate+1

Mechanism of Action / Functional Role

The primary functional role of UNC7938 is to promote endosomal escape of oligonucleotides or macromolecular cargos. Here’s how:

1. Destabilizing endosomal membranes
   UNC7938 is thought to destabilize the lipid bilayer of endosomal compartments. This “priming” increases the tendency of endosomal membranes to leak or allow contents (e.g. oligonucleotides) to escape into the cytosol. American Chemical Society Publications+4aobious.com+4OUP Academic+4

2. Synergism with cell-penetrating peptides (CPPs)
   In systems where cargos are conjugated or associated with CPPs, UNC7938 enhances the leakage activity of CPPs (i.e. helps CPP-mediated escape). PMC+2American Chemical Society Publications+2

3. Selective over more generic agents
   It is mechanistically distinct from classical “proton sponge / osmotic swelling” agents like chloroquine or other cationic amphiphiles. In comparative assays, UNC7938 markedly boosted ASO activity (reporter assays) at concentrations where chloroquine failed to do so. OUP Academic+1
   The idea is that instead of primarily relying on osmotic swelling, UNC7938 more directly perturbs membrane stability. MDPI+2aobious.com+2

4. In vivo enhancement of ASO therapies
   In preclinical models (e.g. mdx mice, a model for Duchenne muscular dystrophy), co-treatment with UNC7938 + ASO led to improved exon skipping, better target correction, and functional benefits (e.g. improved cardiac parameters) compared to ASO alone. MDPI+3PMC+3PMC+3

Benefits and Limitations / Challenges

Benefits / advantages:

• Using a small molecule OEC like UNC7938 can potentially be applied broadly (i.e. with many ASOs or siRNAs) without needing to chemically modify each oligonucleotide. OUP Academic+1

• It can boost the efficiency of delivery in systems where endosomal trapping is a bottleneck. PMC+3PMC+3MDPI+3

• In animal studies, it has shown functional improvements without overt organ toxicity (in some reports) at tolerated doses. PMC+2MDPI+2

Limitations / risks / challenges:

• Cytotoxicity — In vitro, certain concentrations of UNC7938 can cause cell death (~90% in some settings). The membrane disruption effect that helps escape can also be harmful. MDPI+3OUP Academic+3PMC+3

• Dose window — There is likely a narrow therapeutic window between beneficial membrane perturbation and outright toxicity.

• Incomplete mechanistic understanding — The exact molecular interactions (which lipids, which endosomal compartments, how it interacts with the lipid bilayer) remain under investigation.

• Delivery specificity / off-target effects — Membrane destabilization is a fairly unspecific mechanism; unwanted leakage or damage in non-target cells is a concern.

• Translation to human/clinical use — So far, most studies are preclinical (cell culture, rodent models). Safety, pharmacokinetics, and effectiveness in humans remain to be demonstrated.

0°C (short term), -20°C (long term), desiccated

UNC7938; UNC-7938; UNC 7938; UNC10217938A

1) Jason Allen et al., Cytosolic Delivery of Macromolecules in Live Human Cells Using the Combined Endosomal Escape Activities of a Small Molecule and Cell Penetrating Peptides, ACS Chem. Biol. 2019, 14, 12, 2641–2651