In vivo validation of intramolecular bivalent glues targeting PSMA reveals potent and tissue-selective BRD4 degradation in prostate cancer.
5 affiliations
- 1Lachman Institute for Pharmaceutical Development, School of Pharmacy, University of Wisconsin-Madison, WI 53705, USA.
- 2Department of Medical Physics, University of Wisconsin School of Medicine and Public Health, WI 53792, USA.
- 3Department of Radiology, University of Wisconsin School of Medicine and Public Health, WI 53792, USA.
- 4Carbone Cancer Center, University of Wisconsin-Madison, WI 53792, USA.
- 5Department of Chemistry, University of Wisconsin-Madison, WI 53706, USA.
Abstract
Various approaches have been explored to address the on-target, off-tissue toxicity of PROTACs and molecular glues, but most fall short in achieving robust in vivo selectivity and efficacy. In this study, we introduce a delivery strategy that enables tissue-selective deployment of an ultra-potent, picomolar-active DCAF16-recruiting intramolecular bivalent glue (IBG3) for BRD4 degradation in prostate cancer models by targeting the prostate-specific membrane antigen (PSMA). We first introduced rational modifications to IBG3 to install a suitable conjugation handle for PSMA ligand attachment, and incorporated a cathepsins-sensitive cleavable linker together with a dual functional polycarboxylate linker that enhances PSMA binding while suppressing passive diffusion. Selective BRD4 degradation was validated by multiple orthogonal assays in vitro and in vivo. The lead conjugate IBG-P3 achieved 79.8% tumor growth inhibition at 0.01 mg/kg in PC3-PIP xenografts, while an epimeric control lacking PSMA binding was inactive. Importantly, robust antitumor efficacy was further confirmed in an endogenous PSMA-expressing LNCaP xenograft model, where IBG-P3 achieved 72.6% tumor growth inhibition at a dose as low as 0.001 mg/kg, significantly outperforming the parent compound IBG3. This study provides the first in vivo validation of IBG degrader and establishes a preclinical framework for PSMA-guided delivery of potent degraders.
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BibTeX
@article{cai2026vivo,
title = {{In vivo validation of intramolecular bivalent glues targeting PSMA reveals potent and tissue-selective BRD4 degradation in prostate cancer.}},
author = {Deqin Cai and Chunrong Li and Malick Bio Idrissou and Nina J Hawkins and Ramesh Mudududdla and Xuankun Chen and Thao-Vy T Nguyen and Xiaolei Li and Reinier Hernandez and Weiping Tang},
journal = {Acta pharmaceutica Sinica. B},
year = {2026},
month = aug,
doi = {10.1016/j.apsb.2026.08.008},
url = {https://europepmc.org/article/MED/42948766},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - In vivo validation of intramolecular bivalent glues targeting PSMA reveals potent and tissue-selective BRD4 degradation in prostate cancer.
AU - Deqin Cai
AU - Chunrong Li
AU - Malick Bio Idrissou
AU - Nina J Hawkins
AU - Ramesh Mudududdla
AU - Xuankun Chen
AU - Thao-Vy T Nguyen
AU - Xiaolei Li
AU - Reinier Hernandez
AU - Weiping Tang
PY - 2026
DA - 2026/08/11
JO - Acta pharmaceutica Sinica. B
DO - 10.1016/j.apsb.2026.08.008
UR - https://europepmc.org/article/MED/42948766
AB - Various approaches have been explored to address the on-target, off-tissue toxicity of PROTACs and molecular glues, but most fall short in achieving robust in vivo selectivity and efficacy. In this study, we introduce a delivery strategy that enables tissue-selective deployment of an ultra-potent, picomolar-active DCAF16-recruiting intramolecular bivalent glue (IBG3) for BRD4 degradation in prostate cancer models by targeting the prostate-specific membrane antigen (PSMA). We first introduced rational modifications to IBG3 to install a suitable conjugation handle for PSMA ligand attachment, and incorporated a cathepsins-sensitive cleavable linker together with a dual functional polycarboxylate linker that enhances PSMA binding while suppressing passive diffusion. Selective BRD4 degradation was validated by multiple orthogonal assays in vitro and in vivo. The lead conjugate IBG-P3 achieved 79.8% tumor growth inhibition at 0.01 mg/kg in PC3-PIP xenografts, while an epimeric control lacking PSMA binding was inactive. Importantly, robust antitumor efficacy was further confirmed in an endogenous PSMA-expressing LNCaP xenograft model, where IBG-P3 achieved 72.6% tumor growth inhibition at a dose as low as 0.001 mg/kg, significantly outperforming the parent compound IBG3. This study provides the first in vivo validation of IBG degrader and establishes a preclinical framework for PSMA-guided delivery of potent degraders.
SN - 2211-3835
SN - 2211-3843
ER -