Oro Therapeutics™
Developing peptide-drug conjugates (PDCs) to exploit the distinct enzymatic properties of cancer cells.
Oro Therapeutics™
Developing peptide-drug conjugates (PDCs) to exploit the distinct enzymatic properties of cancer cells.
Over-expression of hydrolytic enzymes in cancer cells
aminopeptidases sit at the crossroads of fundamental processes of cancer cells dependencies
Cancer cells divide rapidly and ramp up their metabolism to produce the proteins, DNA, and energy needed for continuous growth. This makes them heavily reliant on amino acids—not just as protein building blocks, but also as sources of energy and structure. Normal fast-growing cells, like those in the mucosa or hair follicles, also use more amino acids but remain under strict control. They can slow or pause growth when nutrients are scarce, adjusting to the body’s signals. Cancer cells, however, lack this flexibility. Their constant demand makes them “addicted” to amino acids, and when supply runs low, they cannot survive.
By ramping up aminopeptidase activity, cancer cells create a self-serving supply chain: they break down proteins within the cell faster, releasing extra amino acids to fuel their uncontrolled growth. This over-expression helps cancer cells survive in nutrient-poor environments, resist stress, and maintain their rapid metabolism. In contrast, normal cells usually keep aminopeptidase activity at balanced levels. They don’t need to overproduce these enzymes because their growth is regulated, and they can pause when nutrients are limited.
Emerging evidence supports the rationale of leveraging this elevated aminopeptidase activity as a targeted approach for new oncology treatments.
Three different approaches to target aminopeptidases
1) Aminopeptidase inhibition, cutting off the amino acid supply that tumors depend on
2) Direct targeting of overexpressed aminopeptidases in cancerous tissue, homing therapies directly to tumor vasculature enriched with aminopeptidases such as CD13/ANPEP
3) Leveraging the hyper-active aminopeptidase activity inside cancer cells to hydrolyze a linker in a peptide-drug-conjugate to release a toxic payload directly into the cancer cell
Learn More (source material)
Sarah A. Holstein, Caroline A. Heckman, Faith E. Davies, Gareth J. Morgan, Stefan Svensson Gelius, Fredrik Lehmann.
Aminopeptidases in Cancer, Biology and Prospects for Pharmacological Intervention,
Current Cancer Drug Targets,
Volume 23, Issue 1, 2023
how our peptide-drug-conjugates work
Step 1: Getting Inside the Tumor Cell
The Peptide-drug-conjugate is designed to be lipophilic, meaning it “loves fat." This is important because every cell in the body is surrounded by a membrane made of fatty molecules (lipids). Many drugs struggle to cross this barrier, but lipophilic molecules can move through more easily. Passive diffusion is when small molecules naturally move across the cell membrane from areas where they’re more concentrated (outside the cell) to where they’re less concentrated (inside the cell). Because the Peptide-drug-conjugate is both lipophilic and small, it can passively diffuse into the tumor cell without needing pumps or transporters.
Step 2: Activation Inside the Cell
Once inside a cancer cell, the Peptide-drug-conjugate encounters the upregulated aminopeptidases. These enzymes are present in many tissues but are found in especially high levels inside tumor cells. Aminopeptidases act like molecular scissors to the Peptide Drug Conjugate's linker. In this case, they hydrolyze the linker holding the compound together, releasing the powerful cytotoxic payload. This step is called precision activation, because the drug stays inactive while circulating in the body and only becomes fully active once it’s inside the cancer cell. Moreover, if the PDC is pulled into a cell without over-expressed aminopeptidases, the cell lacks the molecular "scissors" to separate the peptide from the cytotoxic agent.
Step 3: Payload Gets Trapped Inside and Creates a Thermodynamic "Sink" Effect
The released cytotoxic payload is hydrophilic—it dissolves in water but cannot cross fatty cell membranes. Once activated inside the tumor cell, it becomes trapped, unable to exit the way the lipophilic PDC entered. This trapping creates an irreversible sink: intracellular levels of the payload keep rising while extracellular levels remain lower. From a thermodynamic perspective, the system seeks equilibrium, but since the payload cannot diffuse out, the only way to balance is by drawing more lipophilic PDC into the cell, where it is converted and trapped. The result is a self-reinforcing gradient—continuous uptake of PDC and progressive accumulation of cytotoxic payload inside the cancer cell.
Step 4: Damaging the Cancer Cell’s DNA and killing the cancer cell
The activated cytotoxic payload binds to and cross-links DNA, preventing the cell from copying its genetic code. Deprived of intact DNA, the cancer cell can no longer divide or repair itself and ultimately dies. Because this hydrolysis and payload release occur only inside the cell, the Peptide-drug-conjugate delivers its lethal effect precisely where it’s needed. By restricting activation to tumor cells with high aminopeptidase activity, the therapy achieves greater selectivity than conventional chemotherapy, limiting collateral damage to normal tissues.
in vitro potency of oro-352
IC50 is a key indicator of in vitro potency. The lower the IC50, the more potent the drug is at inhibiting cell growth. Here, ORO-352 illustrates a ~10x increase in potency as compared to the cytotoxic payload alone
A variety of cancers exhibit upregulated aminopeptidases
About Oro Therapeutics
Our Mission
At Oro Therapeutics, our name reflects both the enduring qualities of gold and the transformative process of mountain building (orogeny). Gold embodies catalytic power, enabling precise reactions that mirror our pursuit of therapies designed to act exactly where needed. It also symbolizes illumination and guidance, capturing our commitment to bringing clarity and breakthroughs to cancer treatment. And like gold’s rarity and uniqueness, we aim to develop therapies that stand apart from conventional approaches. The concept of orogeny reminds us that lasting change is shaped through persistence and strength — values that guide our mission to confront cancer with novel mechanisms of action capable of reshaping the landscape of oncology.