Scientists Unlock Cell Entry to Boost Cancer Drug Effectiveness Using CD36 Pathway.

In a major advance that could reshape cancer treatment, scientists have discovered a novel way to enhance the performance of cancer drugs by exploiting a natural cellular entry pathway. The method dramatically increases the internalization of complex therapeutic molecules, particularly a promising class known as PROTACs, by leveraging the protein CD36.

The research, conducted by teams at Duke University School of Medicine, the University of Texas Health Science Center at San Antonio, and the University of Arkansas, focuses on solving a long-standing challenge in cancer drug development: how to get large drug molecules into cells efficiently. The findings, published on April 17 in Cell, demonstrate that redirecting these drugs to enter cells through the CD36 protein boosts their uptake by 7.7 to 22.3 times. In animal models, this translated to significantly stronger tumor suppression.

The approach, termed chemical endocytic medicinal chemistry (CEMC), utilizes the process of endocytosis—where cells engulf substances from their surroundings—to deliver drugs that are traditionally too large to enter cells by passive diffusion. CD36, a protein naturally present on the surface of cells in tissues such as the intestine, lungs, skin, eyes, and even parts of the brain, plays a key role in facilitating this active transport.

“This discovery opens a new door in drug design,” said Dr. Hui-Kuan Lin, a professor of pathology and cancer biology at Duke University. “Many drugs previously dismissed due to poor absorption may now be revisited and optimized for therapeutic use.”

The strategy is especially impactful for a group of molecules known as bRo5 compounds, which includes PROTACs. These are large, targeted cancer drugs designed to degrade specific proteins inside cells. Typically, molecules exceeding 500 daltons in size are thought to struggle with cell entry—a guideline known as the 'Rule of 5' in pharmacology. The PROTACs used in the study far exceed that threshold, measuring over 1,000 daltons, yet still achieved high uptake and potency through the CD36-dependent method.

Dr. Hong-yu Li, professor of medicinal chemistry at UT-San Antonio, explained, “For years, we assumed molecules this large couldn’t cross cell membranes effectively. Our research shows that by understanding and using the biology of proteins like CD36, we can overcome that barrier.”

The team not only confirmed the method's effectiveness in boosting drug uptake, but also verified that the modified drugs retained essential characteristics such as solubility and stability—both critical for clinical success. Furthermore, the results were reproduced independently across all participating research labs, adding confidence to the findings.

Traditional cancer drugs often work by blocking specific enzyme activity in cancer-related proteins. However, these proteins can have multiple roles, and simply inhibiting one function may not fully stop cancer progression. In contrast, PROTACs offer a more comprehensive approach by degrading the entire target protein, potentially leading to better outcomes and reducing the risk of drug resistance.

Eight oral PROTAC drugs are currently in clinical trials, including one in a Phase 3 study aimed at targeting estrogen receptors in breast cancer. The new design strategy using CD36 could supercharge these efforts by enabling more efficient drug delivery to the right cells.

Dr. Zhiqiang Qin, associate professor at the University of Arkansas for Medical Sciences, added that while further testing and clinical trials are required, the results mark a significant leap forward in drug development for cancer and other diseases involving harmful proteins.

Researchers believe that this breakthrough could pave the way for broader applications, potentially transforming the future of treatments for neurodegenerative disorders and other complex conditions once thought beyond the reach of traditional drug designs.

Source: https://www.sciencedaily.com/releases/2025/04/250417145012.html

This is non-financial/medical advice and made using AI so could be wrong.