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In vivo validation of intramolecular bivalent glues targeting PSMA reveals potent and tissue-selective BRD4 degradation in prostate cancer
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DOI：10.1016/j.apsb.2026.08.008.png)
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Abstract
En 中文
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.
Keywords:
PSMA
Intramolecular bivalent glue
BRD4
Prostate cancer
Precision degradation
PDC
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