DNA is usually taught as a tidy double helix: two strands neatly twisted around each other, carrying genetic instructions that cells read and copy. But in reality, DNA is far messier than textbook diagrams suggest.
Under certain conditions, stretches of DNA rich in the base guanine can fold in on themselves, forming compact, knot-like shapes known as G-quadruplexes, or G4 structures. Instead of the familiar two-stranded helix, four strands of DNA stack together, creating a three-dimensional structure that can physically block the cell’s transcription machinery.
“These G-quadruplex structures are found throughout the genome, but they’re particularly enriched in promoter regions of important genes, where they act as regulatory elements,” Daniel Tillett, the CEO and Managing Director of Racura Oncology, explained to DDN.
He added, “Structurally, they’re often described as having a flattened, football-like shape, that is highly dynamic. They form and then come apart again, with a melting temperature typically around 30°C, although this varies depending on the sequence and cellular environment.”
Genome-wide mapping has revealed over 700,000 regions that could potentially fold into G4 structures. Many of these structures sit in gene promoters and enhancers, including those controlling key cancer genes such as c-MYC (cellular myelocytomatosis) and RAS (Rat sarcoma). Others have been found in non-coding RNAs, untranslated regions of messenger RNAs, and even mitochondrial DNA.
In theory, this makes G4 sites an appealing therapeutic target. Lock one of these structures in place, and a cancer-driving gene may never be transcribed in the first place. In practice, however, the field has struggled to turn that idea into medicine. Despite nearly 3,000 reported G4-binding molecules, very few have advanced into clinical trials, and none have entered routine oncology practice.
That may be about to change. A decades-old anticancer drug has been revived and reformulated by Racura, and shown to effectively silence a key cancer gene by stabilizing G4 structures within the promoter region.
Rediscovering an overlooked mechanism
Racura’s lead candidate, RC220, is a reformulated version of bisantrene, an anticancer drug first developed by Lederle Laboratories in the 1970s. Bisantrene showed activity across multiple cancer indications and was tested in dozens of clinical trials involving more than 1,500 patients. It was even approved in France for the treatment of acute myeloid leukaemia (AML). However, the drug wasn’t perfect.
Our drug has a property that’s very un-druglike. In fact, if it were discovered today, it probably wouldn’t even make it into a mouse, because it’s completely insoluble at physiological pH.
— Daniel Tillett, Racura Oncology
“Our drug has a property that’s very un-druglike. In fact, if it were discovered today, it probably wouldn’t even make it into a mouse, because it’s completely insoluble at physiological pH,” Tillett explained. “As soon as you inject it, it crystallizes out in the vein and causes all sorts of problems. There are reports in the old literature of patients pulling catheters out of their arms, screaming in pain, with the vein essentially destroyed.”
After extensive preclinical work, Racura’s scientists discovered that bisantrene binds and stabilizes G4 DNA structures, including in the promoter region of the c-MYC oncogene. By locking those structures in place, the drug suppresses c-MYC transcription, driving MYC protein levels down to near zero within hours.
“c-MYC has long been something of a holy grail in oncology,” said Tillett. “It is a master regulator of cell growth. Once activated, MYC switches on roughly 2,000–4,000 genes involved in cell replication, effectively giving the cell permission to divide. What makes it especially compelling is that it is arguably the closest thing to a universal target in oncology, with around 70 percent of tumors showing c-MYC overexpression or dysregulation.”
MYC has been notoriously difficult to target in oncology because the protein is intrinsically disordered, lacks a defined binding pocket for conventional small molecule drugs, and does not possess enzymatic activity. For decades, those features have made MYC effectively undruggable. By stabilizing G4 structures in the c-MYC promoter, RC220 offers a rare route to suppressing one of cancer’s most central drivers.
Why G-quadruplex drugs have failed before
While a significant number of ligands targeting G4s have been developed as drugs, most have reported poor drug-like properties, such as high molecular weights and hydrophobic nature.
According to Tillett, the challenge is not just selectivity or toxicity, but chemistry itself. “What we’ve realized is that the chemical properties that make a really good G-quadruplex binder are the same properties that make a molecule poorly soluble in blood. Modern medicinal chemistry filters those molecules out very early.”
As a result, many contemporary G4 ligands are chemically compromised — designed to look drug-like at the expense of binding strength. Bisantrene, by contrast, emerged from a time when compounds were pushed forward based on activity rather than developability.
“It really comes down to the era it was developed in,” explained Tillett. “Now, medicinal chemists are very good at knowing what a drug should look like as they’re designing it. In the old days, chemists would just make something, put it into a mouse, and see what happened. It was entirely empirical — they had no idea what was actually going on.”
Racura’s key advance was not changing the molecule, but solving its formulation. After several years and millions of dollars of work, the company developed a formulation that keeps RC220 in solution long enough to be safely delivered, without altering its pharmacokinetics or pharmacodynamics.
“That was critical,” Tillett said. “We wanted the drug to behave exactly the same as it did historically — just without the crystallization problem.”
From rediscovery to the clinic
RC220 is already deep into clinical development. Racura is advancing three separate programs, each exploiting MYC biology in a different context.
The most advanced is a Phase 3 trial in AML, where bisantrene has historically shown strong clinical activity. With the benefit of hindsight, the reason is likely because roughly 90 percent of AML cases are driven by MYC.
“AML gives us a very clean human proof-of-concept,” Tillett said. “You can sample cancer cells directly from the blood and show that the drug is hitting the exact gene you’re aiming for, at the right concentration, in patients.”
The second program targets epidermal growth factor receptor non-small cell lung cancer (EGFR-NSCLC) in combination with the tyrosine kinase inhibitor osimertinib. The goal here is to delay, or prevent, the development of resistance to osimertinib.
“At diagnosis, patients who have the right mutation go onto the drug and usually respond very well, with relatively few side effects,” Tillett said. “The problem is that the response only lasts for a finite period.”
That period can range from a few months to several years, but resistance is ultimately inevitable. When treatment fails, options are limited. Chemotherapy is often the only remaining choice, and survival after failure is typically around six months, with many patients moving directly to palliative care.
“That’s the unmet need we’re trying to address,” Tillett continued. “Our approach is to combine our drug with osimertinib to keep it working for longer. Using circulating tumor DNA, we can detect when resistance is about to emerge and come in the last few months before failure — when intervention actually matters.”
Racura’s third program takes advantage of a more unexpected property: RC220 appears to protect the heart from the cardiotoxicity caused by conventional chemotherapy. This includes doxorubicin, a current standard of care chemotherapeutic. In a previous breast cancer study comparing bisantrene with doxorubicin, bisantrene was associated with significantly lower rates of serious cardiac damage (4 percent versus 23 percent).
“Our drug is adding to the anti-cancer activity, while at the same time protecting heart muscle cells from the damage doxorubicin causes,” Tillett explained. “For people working in cardio-oncology, this has been something of a dream scenario for a long time. There are drugs that protect the heart, but they also protect the cancer, which makes oncologists understandably reluctant to use them.”
The reason comes down to how MYC behaves in different cell types. “In the heart — which is made up of non-dividing cells — MYC behaves very differently than it does in dividing cancer cells. By suppressing c-MYC expression in heart cells, we can prevent doxorubicin from causing the double strand DNA breaks that lead to cardiac damage.”
A broader lesson for drug discovery
Whether RC220 proves to be a one-off success or the beginning of a broader shift remains an open question. Tillett believes the real lesson may be less about G4 ligands themselves and more about how the industry approaches drug discovery.
“There are a lot of very good drugs that got lost for non-scientific reasons — company failures, strategy changes, patent timing,” he said. “Drug development is one of the few fields where there are effectively $100 bills lying on the street and nobody bothers to bend down and pick them up. If you go about it the right way, there are a lot of opportunities.”
Rather than betting exclusively on novel molecules with long odds of success, Racura’s approach started with a drug that was already known to work in humans. Working backwards from there, they could begin to understand and optimize it.
“In oncology, the biggest reason drugs fail is that they don’t work in patients,” Tillett said. “If you start with something that already does, you’re in a much better position.”
