Related Experiment Video
Updated: Sep 18, 2025
Phosphopeptide Enrichment Coupled with Label-free Quantitative Mass Spectrometry to Investigate the Phosphoproteome in Prostate Cancer
Published on: August 2, 2018
Discovery of high-affinity ligands for prostatic acid phosphatase via DNA-encoded library screening enables targeted
Tony Georgiev1, Francesca Migliorini1, Andrea Ciamarone1,2
1R&D Department, Philochem AG, Otelfingen, Switzerland.
Abstract:
Improving the specificity of prostate cancer treatment requires ligands that bind selectively and with ultra-high affinity to tumour-associated targets absent from healthy tissues. Prostatic acid phosphatase has emerged as an alternative target to prostate-specific membrane antigen, as it is expressed in a broader subset of prostate cancers and is not detected in healthy organs such as the salivary glands and kidneys. Here, to discover selective binders to prostatic acid phosphatase, we constructed two DNA-encoded chemical libraries comprising over 6.7 million small molecules based on proline and phenylalanine scaffolds. Screening against the purified human prostatic acid phosphatase yielded OncoACP3, a small organic ligand with picomolar binding affinity. When radiolabelled with lutetium-177, OncoACP3 selectively accumulated in enzyme-expressing tumours with a long residence time (biological half-life greater than 72 h) and a high tumour-to-blood ratio (>148 at 2 h after administration). Lutetium-177-labelled OncoACP3 cured tumours in mice at low, well-tolerated doses. Its conjugation to the cytotoxic agent monomethyl auristatin E facilitated tumour-selective payload deposition, resulting in potent anti-tumour activity. The modular structure of OncoACP3 supports flexible payload delivery for the targeted treatment of metastatic prostate cancer.
Insights
Researchers developed OncoACP3, a novel small molecule ligand targeting prostatic acid phosphatase. This targeted therapy demonstrated potent anti-tumour activity in mice, offering a promising new approach for metastatic prostate cancer treatment.
Area of Science:
- Oncology
- Medicinal Chemistry
- Radiopharmaceutical Science
Background:
- Prostate cancer treatment requires highly specific ligands targeting tumour-associated antigens.
- Prostatic acid phosphatase (PAP) is a promising target due to its expression in a broad range of prostate cancers and absence in healthy organs.
- Current targets like prostate-specific membrane antigen (PSMA) have limitations in specificity and expression profile.
Purpose of the Study:
- To discover selective, high-affinity ligands for prostatic acid phosphatase (PAP).
- To develop targeted therapies for metastatic prostate cancer using novel small molecules.
- To evaluate the therapeutic potential of PAP-targeting ligands in preclinical models.
Main Methods:
- Construction of two DNA-encoded chemical libraries (over 6.7 million small molecules) based on proline and phenylalanine scaffolds.
- Screening of libraries against purified human prostatic acid phosphatase to identify selective binders.
- Radiolabelling of the lead compound (OncoACP3) with lutetium-177 for in vivo studies.
- Assessment of tumour accumulation, residence time, and anti-tumour efficacy in mouse models.
Main Results:
- Identification of OncoACP3, a small organic ligand with picomolar binding affinity for PAP.
- Lutetium-177-labelled OncoACP3 showed selective tumour accumulation, long residence time (>72h half-life), and high tumour-to-blood ratio (>148 at 2h).
- Treatment with lutetium-177-OncoACP3 cured tumours in mice at low, well-tolerated doses.
- Conjugation to monomethyl auristatin E enabled tumour-selective payload delivery and potent anti-tumour activity.
Conclusions:
- OncoACP3 is a highly selective and potent ligand for prostatic acid phosphatase.
- Radiolabelled OncoACP3 demonstrates excellent tumour targeting and therapeutic potential for metastatic prostate cancer.
- The modular design of OncoACP3 allows for flexible payload delivery, supporting targeted therapy development.
More Related Videos
07:32Screening and Identification of Small Peptides Targeting Fibroblast Growth Factor Receptor2 using a Phage Display Peptide Library
Published on: September 30, 2019
06:54MR Molecular Imaging of Prostate Cancer with a Small Molecular CLT1 Peptide Targeted Contrast Agent
Published on: September 3, 2013
