A new scientific breakthrough could dramatically improve cancer treatments by helping bulky, hard-to-deliver drugs enter cells more efficiently.
Researchers from Duke University, the University of Texas Health Science Center at San Antonio, and the University of Arkansas have discovered a way to significantly boost the cellular uptake of a promising class of cancer therapies known as PROTACs. These drugs work by degrading harmful proteins in cells but are often too large to penetrate cell membranes on their own.
The team found that a naturally occurring cell surface protein, CD36, can act as a transporter, helping PROTACs cross the cellular barrier. By modifying the drugs to exploit this transport mechanism, the researchers achieved up to 22.3 times higher drug uptake, resulting in up to 23 times more powerful tumor suppression—all without sacrificing drug stability or solubility. Their findings, published April 17 in Cell, could breathe new life into many large-molecule drugs previously deemed too unwieldy for therapeutic use.
The strategy, termed chemical endocytic medicinal chemistry (CEMC), taps into endocytosis—a natural process cells use to internalize nutrients and molecules. Instead of relying on passive diffusion (the standard approach in drug design), CEMC uses active transport through cell surface receptors like CD36 to carry oversized drugs into the cell.
“Most drug development efforts focus on making molecules small enough to slip through membranes, but this turns that thinking on its head,” said Dr. Hui-Kuan Lin, cancer biology professor at Duke University. “This could rescue many drugs once abandoned for being too large.”
CD36 is widely expressed in various tissues including the intestine, skin, lungs, eyes, and even the brain, making it an ideal candidate for targeted delivery. The method proved especially effective for large drugs known as bRo5 molecules—including PROTACs, which often exceed 1,000 daltons (Da) in size, far beyond the traditional drug size threshold of 500 Da set by the “Rule of 5.”
Until now, drugs of that size were believed to be practically unusable because their size prevented them from entering cells. But in lab and mouse studies, the PROTACs modified to engage with CD36 not only entered cancer cells efficiently but also showed stronger anti-tumor effects, all while maintaining the essential traits of good drugs—stability and solubility.
“This was completely unexpected,” said Dr. Hong-yu Li, professor of medicinal chemistry at UT-San Antonio. “For decades, we didn’t think molecules this large could enter cells effectively.”
The study also demonstrated reproducibility across multiple research teams, with lab results confirmed independently by co-author Dr. Zhiqiang Qin at the University of Arkansas for Medical Sciences.
Beyond enhancing PROTACs, this discovery could revolutionize how researchers approach the development of many other large, complex drugs. PROTACs themselves represent a major leap in targeted therapy because, unlike traditional drugs that merely block a protein’s function, PROTACs remove the protein entirely—potentially leading to stronger and more durable responses.
“Since PROTACs eliminate their targets instead of just blocking them, they may reduce the chance of resistance and achieve longer-lasting effects,” said Dr. Lin.
These therapies are already in development for cancer and neurodegenerative diseases like Parkinson’s. Notably, eight oral PROTAC drugs are currently in clinical trials, including a Phase 3 trial evaluating a PROTAC for breast cancer.
While the findings need further validation in clinical trials, the potential is vast. By leveraging natural cellular entry routes like CD36, researchers may finally be able to unlock the power of a vast library of once-dismissed drug candidates—ushering in a new era of large molecule drug design with applications that stretch well beyond cancer.
By Impact Lab
