Tissue distribution and retention drives efficacy of rapidly clearing VHL-based PROTACs

• Published in: Communications medicine 2024-05, Vol.4 (1), p.87-87, Article 87
• Main Authors: Zhang, Donglu, Ma, Bin, Dragovich, Peter S., Ma, Li, Chen, Shu, Chen, Eugene C., Ye, Xiaofen, Liu, Joyce, Pizzano, Jennifer, Bortolon, Elizabeth, Chan, Emily, Zhang, Xing, Chen, Yi-Chen, Levy, Elizabeth S., Yauch, Robert L., Khojasteh, S. Cyrus, Hop, Cornelis E. C. A.
• Format: Article
• Language: English
• Subjects: 59/5; 631/154/152; 64/110; 64/60; 692/308/153; Bile; Drug dosages; Feces; Humidity; Laboratory animals; Ligands; Medicine; Medicine & Public Health; Metabolism; Permeability; Pharmacokinetics; Plasma; Proteins; Radiography; Retention; Tumors; Urine
• ISSN: 2730-664X; 2730-664X
• DOI: 10.1038/s43856-024-00505-y

Background Proteolysis-targeting chimeras (PROTACs) are being developed for therapeutic use. However, they have poor pharmacokinetic profiles and their tissue distribution kinetics are not known. Methods A typical von Hippel-Lindau tumor suppressor (VHL)—PROTAC 14 C-A947 (BRM degrader)—was synthesized and its tissue distribution kinetics was studied by quantitative whole-body autoradiography (QWBA) and tissue excision in rats following IV dosing. Bile duct-cannulated (BDC) rats allowed the elucidation of in vivo clearance pathways. Distribution kinetics was evaluated in the tissues and tumors of mice to support PK-PD correlation. In vitro studies enabled the evaluation of cell uptake mechanisms and cell retention properties. Results Here, we show that A947 quickly distributes into rat tissues after IV dosing, where it accumulates and is retained in tissues such as the lung and liver although it undergoes fast clearance from circulation. Similar uptake/retention kinetics enable tumor growth inhibition over 2–3 weeks in a lung cancer model. A947 quickly excretes in the bile of rats. Solute carrier (SLC) transporters are involved in hepatocyte uptake of PROTACs. Sustained BRM protein degradation is seen after extensive washout that supports prolonged cell retention of A947 in NCI-H1944 cells. A947 tissue exposure and pharmacodynamics are inversely correlated in tumors. Conclusions Plasma sampling for VHL-PROTAC does not represent the tissue concentrations necessary for efficacy. Understanding of tissue uptake and retention could enable less frequent IV administration to be used for therapeutic dosing. Plain language summary Proteolysis-targeting chimeras (PROTACs) are a type of potential cancer medicine designed to target proteins primarily present in tumours. There is limited data on how it is absorbed, distributed, metabolised and excreted from tissues. Here, we studied the tissue distribution of synthetic PROTAC molecules labelled with radioactivity following intravenous injection in rodent models. We find that PROTAC can rapidly distribute to target tumour tissues and its prolonged retention within the tumour cells can contribute to prevention of further tumour growth, as demonstrated in the lung cancer model. These findings suggest the evaluation of PROTAC therapeutic effectiveness directly from tumour tissues provides more relevant assessment than sampling from blood circulation, which may have implications for a reduction in intravenous dosing. Zhang e