{"id":2810,"date":"2026-06-23T17:44:42","date_gmt":"2026-06-23T17:44:42","guid":{"rendered":"https:\/\/magazines.uthscsa.edu\/cancer-center\/?p=2810"},"modified":"2026-06-23T18:11:56","modified_gmt":"2026-06-23T18:11:56","slug":"drug-discovery-breakthrough-for-large-and-polar-drugs-discovery-of-chemical-endocytosis-could-redefine-precision-medicine","status":"publish","type":"post","link":"https:\/\/magazines.uthscsa.edu\/cancer-center\/2026\/06\/23\/drug-discovery-breakthrough-for-large-and-polar-drugs-discovery-of-chemical-endocytosis-could-redefine-precision-medicine\/","title":{"rendered":"Drug-discovery breakthrough for large and polar drugs: Discovery of chemical endocytosis could redefine precision medicine"},"content":{"rendered":"

By Claire Kowalick<\/p>\n

A team of scientists, notably Zhengyu Wang, PhD, assistant professor in the department of pharmacology at The University of Texas at San Antonio and the Barshop Institute, led by Hong-yu Li, PhD, professor of medicinal chemistry and chemical biology with the department of pharmacology and the Barshop Institute, together with two other teams led by Hui-kuan Lin, PhD, from Duke University and Zhiqiang Qin, MD, PhD, from the University of Arkansas for Medical Sciences, uncovered the mechanism of cellular uptake for large and polar drugs and devised a novel strategy to optimize the capacity of drug delivery into these cells.<\/p>\n

Published online in Cell, the study creates a strategy called chemical endocytic medicinal chemistry that may revolutionize how endocytic drugs in the future are designed and developed. Other contributors to this publication include Bo-Syong Pan, PhD, Rajesh Manne, PhD, and Che-Chia Hsu, PhD, (Duke); Jungang Chen, PhD, Phuc Tran, PhD, Tsigereda Weldemichael, PhD, and Jingwei Shao, PhD, (UAMS); and Dongwen Lv, PhD, Minmin Wang, PhD, Wei Yan, PhD, assistant professor, Hongfei Zhou, PhD, Gloria M. Martinez, PhD, Robert Hromas, MD, FACP, dean of the Joe R. and Teresa Lozano Long School of Medicine at UT San Antonio and Daohong Zhou, MD, professor, associate director for drug development at the Mays Cancer Center and director of the Center for Innovative Drug Discovery at UT San Antonio.<\/p>\n

\u201cChemical endocytic medicinal chemistry has the potential to impact every aspect of endocytic drugs from drug discovery and development to clinical practice,\u201d said Li.<\/p>\n

In this novel process, drug molecules are designed to better engage with CD36, a protein receptor found on the surface of many cells. By optimizing chemical interactions with CD36, the team was able to enhance the natural function of CD36, essentially escalating up the gateway for larger and polar drug compounds to enter the cell.<\/p>\n

\u201cThis innovative chemical approach can potentially make any intravenous drug able to be taken orally. It can also promote any drug crossing the blood-brain barrier. This will remarkably broaden the number of agents we have to treat brain cancer or dementia,\u201d
\nsaid Robert A. Hromas, MD, FACP, dean of the Joe R. and Teresa Lozano Long School of Medicine at UT
\nSan Antonio.<\/p>\n

Overcoming the \u2018Rule of 5\u2019 barrier for drug development<\/strong><\/span><\/h3>\n

Small-molecule drugs have been limited due to the belief that passive diffusion was the primary mechanism of cell entry. One of the most promising developments in recent years in drug discovery is induced proximity. This drug discovery process utilizes molecules to bring proteins together to create a desired protein interaction and\/or chemical reaction. Until now, molecules larger than 500 Daltons (Da) were believed to be practically unusable due to the challenges of cell access and bioavailability. This greatly restricted the kinds of compounds that could be developed as induced proximity drugs.<\/p>\n

This new mechanistic discovery bypasses this limitation by chemically enhancing CD36-mediated uptake, amplifying the efficiency of larger and polar molecules to enter target cells. CD36 was known to play a role in lipid transport and metabolism, but the team found it also had unexpected potential for promoting cellular uptake of large and polar chemical drugs.<\/p>\n

\u201cThis 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,\u201d said study author Hui-Kuan Lin, PhD, a cancer biology researcher and professor in the Department of Pathology at Duke University School of Medicine.<\/p>\n

\"Hong-yu\u201cThe Chemical endocytic medicinal chemistry has the potential to impact every aspect of endocytic drugs from drug discovery and development to clinical practice.\u201d
\n<\/span><\/p><\/blockquote>\n

\u2013 Hong-yu Li, PhD<\/span>
\n
\n<\/strong><\/span><\/p>\n

Provocative but well-validated results<\/strong><\/span><\/h3>\n

In the study, the team first discovered and validated the CD36-mediated endocytic uptake of large and polar chemical compounds with sizes between 543 and 2,145 Da and then tested the efficacy of optimized CD36 action on the cellular uptake of proteolysis targeting chimeras (PROTACs), a class of large molecular compounds that includes an E3 ligase protein-binding domain, a binding domain for a target protein, and a linker. The team was astonished at the speed, effective uptake and potency of the compounds when utilizing the chemical endocytic medicinal chemistry strategy through CD36 interaction.<\/p>\n

\u201cThis was completely unexpected in the research field,\u201d said Li. \u201cFor decades, it was thought that molecules this large couldn\u2019t cross membranes effectively, since the endocytic cellular uptake of chemicals was unknown. Through chemistry and biology, we identified CD36 as a protein for uptake and optimized chemicals better engaging with CD36 to internalize these drugs to more efficiently reach target proteins,\u201d said Li.<\/p>\n

The key experimental results were independently reproduced by each of the teams involved in the study.<\/p>\n

\u201cAs the research conclusion is so provocative, we verified the key results multiple times,\u201d said Li. \u201cThe implications of this for drug discovery and development are enormous.\u201d<\/p>\n

Rewriting the rules: Implications for drug development and the FDA<\/span><\/strong><\/h3>\n

Traditional drug development is an extensive, expensive process focused on optimizing chemical compounds for passive diffusion into a cell by considering its contradictory characteristics of permeability, solubility and stability. This new process for endocytic drugs represents a paradigm shift that removes these challenges by using the membrane receptor-mediated cellular entry.<\/p>\n

\u201cThis breakthrough discovery will force us to rethink how we approach efficacy and pharmacokinetics and toxicity,\u201d said Li. \u201cWe believe it will also eventually change how regulatory agencies like the [Food and Drug Administration] FDA evaluate and approve new endocytic drugs.\u201d<\/p>\n

In the next 10 to 20 years, this may become a foundational approach in drug discovery and a new research field within medicinal chemistry.<\/span><\/p><\/blockquote>\n

Patient stratification based on different CD36 expression<\/strong><\/span><\/h3>\n

By analyzing tissue from prostate cancer patients, the team found CD36 expression levels varied widely. Li said this may explain why different patients respond differently to some cancer medications.<\/p>\n

\u201cBy optimizing CD36 engagement through chemical endocytic medicinal chemistry, we may be able to target cancer and other diseases precisely through precision treatment based on the differential expression of CD36 in various tissues and different individuals,\u201d said Li.<\/p>\n

What comes next<\/span><\/strong><\/h3>\n

Li said that, along with CD36, it is likely that there are additional cell receptors that could be targeted for chemical endocytosis, which Li\u2019s laboratory continues to explore. He said the field of drug development may be significantly different in the next couple of decades due to this discovery and the potential it brings to induced proximity drugs. Li said there are high levels of CD36 receptors in intestine, brain and skin cells as well, so the chemical endocytosis strategy brings promise for better drug delivery that provides higher oral bioavailability, effectively bridges the blood-brain barrier or enters through the skin.<\/p>\n

\u201cIn the next 10 to 20 years, this may become a foundational approach in drug discovery and a new research field within medicinal chemistry. We feel incredibly lucky to have made this discovery and opened the door to hope for previously untreatable diseases,\u201d said Li.<\/p>\n","protected":false},"excerpt":{"rendered":"

By Claire Kowalick A team of scientists, notably Zhengyu Wang, PhD, assistant professor in the department of pharmacology at The University of Texas at San Antonio and the Barshop Institute, led by Hong-yu Li, PhD, professor of medicinal chemistry and chemical biology with the department of pharmacology and the Barshop Institute, together with two other […]<\/p>\n","protected":false},"author":653,"featured_media":2927,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[12],"magazine":[22],"issue-year":[79],"featured-story":[36],"class_list":["post-2810","post","type-post","status-publish","format-standard","has-post-thumbnail","hentry","category-research","magazine-cancer-center","issue-year-79","featured-story-homepage"],"yoast_head":"\nDrug-discovery breakthrough for large and polar drugs: Discovery of chemical endocytosis could redefine precision medicine - Mays Cancer Center Annual 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