Scientists have found a surprising new way to make certain cancer drugs work dramatically better – by helping them get inside cells more easily.
These drugs, called PROTACs, are often too large to enter cells on their own. But researchers discovered that by guiding them through a natural cell protein called CD36, they could deliver up to 22 times more of the drug, making the treatment far more powerful. In lab and animal studies, this trick led to much stronger tumor suppression without harming the drug’s stability. The finding could revive many promising drugs once thought too bulky to work and change how future treatments are designed.
Boosting PROTAC Uptake
A new scientific breakthrough could lead to more effective cancer treatments by helping certain 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 developed a way to boost the uptake of a promising class of cancer therapies known as PROTACs. These drugs have shown potential but often struggle to reach their targets inside cells because of their large size.
The team found that a naturally occurring protein called CD36 can be used to transport these large molecules into cells. By modifying the drugs to take advantage of this pathway, they were able to deliver between 7.7 and 22.3 times more of the drug into cancer cells – making the treatment up to 23 times more effective, according to a study published today (April 17) in Cell.
In mouse models, this approach led to stronger tumor suppression without compromising the drug’s stability or solubility.
Harnessing CD36 Pathway
The strategy called chemical endocytic medicinal chemistry (CEMC) takes advantage of a natural process where cells “swallow” molecules called endocytosis. It could change the future of drug design – especially for drugs that were once considered too big to work.
“This discovery is important because it could rescue many drugs that were previously considered unusable due to poor absorption and turn them into clinically useful treatments for diseases,” said study author Hui-Kuan Lin, PhD, a cancer biology researcher and professor in the Department of Pathology at Duke University School of Medicine.
Most drug development focuses on tweaking molecules to improve their ability to slip through cell membranes by passive diffusion. But the new strategy takes a different path: using cell surface receptors like CD36 to actively bring drugs inside. CD36 is a protein abundantly found on the surface of cells in the intestine, skin, lungs, eyes, and even some brain cells.
The strategy was particularly successful for a class of complex, large-sized drugs known as bRo5 molecules, such as PROTACs, a type of targeted cancer therapy that breaks down proteins in cells.
Overcoming Size Limitations
These molecules usually have a hard time getting into cells because they’re very large – over 500 dalton (Da). Until now, it was unclear how they entered cells at all. In this study, the PROTAC drugs tested were over 1,000 Da, which is enormous by pharmaceutical standards.
But the modified PROTACs not only entered cells more efficiently but also showed greater tumor-fighting power, all while maintaining their stability and solubility – two crucial factors for effective medicines.
In doing so, the strategy overcomes the ‘Rule of 5’ barrier for drug development which holds that drugs larger than 500 Da are generally ineffective because they struggle to enter cells.
“This was completely unexpected in the research field,” said study author Hong-yu Li, PhD, professor of medicinal chemistry and chemical biology in the Department of Pharmacology at UT-San Antonio.
Reproducibility and Expert Insights
“For decades it was thought that molecules this large couldn’t cross membranes effectively, since the endocytic cellular uptake of chemical compounds was unknown,” Li said. “Through chemistry and biology, we identified CD36 as a protein for uptake and optimized drugs better engaging with CD36 to internalize these drugs to more efficiently reach target protein.”
The results were independently reproduced by each of the teams involved in the study, including lab work led by study author, Zhiqiang Qin, MD, PhD, associate professor of pathology at the University of Arkansas for Medical Sciences.
The findings will need to undergo further testing and evaluation in clinical trials before the strategy can be used in medications given to patients during cancer treatment.
Advantages of PROTAC Therapies
Traditional cancer drugs, like kinase inhibitors, are designed to block just the enzymatic activity of a target protein – basically, they stop the protein from doing one specific job. But they don’t get rid of the protein itself.
However, many proteins have other functions beyond their enzyme activity and those can still help cancer grow and spread. That means the drug isn’t fully stopping the cancer, and over time, the cancer can become resistant to the drug.
“Since PROTACs degrade its target protein and activity, it is expected to achieve more potent efficacy and reduce the possibility of drug resistance in the future,” said Lin, who is also a professor of cancer biology and pharmacology at Duke.
PROTACs are being developed to treat cancer, neurodegenerative diseases like Parkinson’s, and other conditions where eliminating harmful proteins could make a major difference. Eight oral PROTAC drugs are being tested in clinical trials — including a recent Phase 3 trial exploring one as a first-line therapy to break down estrogen receptors in breast cancer tumors.
But the new drug design extends beyond cancer treatment. Researchers say the findings suggest that many other large and complex drugs could be improved using the same strategy.
Reference: “CD36-mediated endocytosis of proteolysis-targeting chimeras” by Zhengyu Wang, Bo-Syong Pan, Rajesh Kumar Manne, Jungang Chen, Dongwen Lv, Minmin Wang, Phuc Tran, Tsigereda Weldemichael, Wei Yan, Hongfei Zhou, Gloria M. Martinez, Jingwei Shao, Che-Chia Hsu, Robert Hromas, Daohong Zhou, Zhiqiang Qin, Hui-Kuan Lin and Hong-Yu Li, 17 April 2025, Cell.
DOI: 10.1016/j.cell.2025.03.036
Additional study authors include co-lead authors Zhengyu Wang, of UT-San Antonio, and Bo-Syong Pan and Rajesh Kumar Manne, of Duke.
The study was supported in part by the National Institutes of Health (R01 CA277682) (R01 CA139429); University of Texas Health San Antonio; Arkansas Research Alliance Endowed Chair Fund; Duke University School of Medicine; Duke Fred and Janet Sanfilippo Distinguished Professorship ; Arkansas Bioscience Institute; Arkansas Breast Cancer Research Program Pilot Award and the Cancer Prevention and Research Institute of Texas.
Never miss a breakthrough: Join the SciTechDaily newsletter.
Follow us on Google and Google News.