Inhibitors of prostate-specific membrane antigen in the diagnosis and therapy of metastatic prostate cancer – a review of patent literature

ABSTRACT

Introduction

Prostate-specific membrane antigen (PSMA), also known as glutamate carboxypeptidase II, is a potential target protein for imaging and treatment of patients with prostate cancer because of its overexpression during metastasis. Various PSMA-targeted imaging and therapeutic probes have been designed and synthesized based on the Lys-urea-Glu motif. Structural modifications have been made exclusively in the linker region, while maintaining the Lys-urea-Glu structure that interacts with S1 and S1ʹ pockets.

Area Covered

This review includes WIPO-listed patents (from January 2017 to June 2020) reporting PSMA-targeted probes based on the Lys-urea-Glu or Glu-urea-Glu structure.

Expert opinion

: PSMA-targeted imaging agents labeled with radionuclides such as fluorine-18, copper-64, gallium-68, and technetium-99m have been successfully translated into clinical phase for the early diagnosis of metastatic prostate cancer. Recently, PSMA-targeted therapeutic agents labeled with iodine-131, lutetium-177, astatine-211, and lead-212 have also been developed with notable progress. Most PSMA-targeted agents are based on the Lys-urea-Glu or Glu-urea-Glu structure, demonstrate strong PSMA-binding affinity in nanomolar range, and achieve diverse structural modifications in the non-pharmacophore pocket. By exploiting the S1 accessory pocket or the tunnel region of the PSMA active site, the in vivo efficacy and pharmacokinetic profiles of the PMSA-targeted agents can be effectively modulated.

KEYWORDS:

• Prostate-specific membrane antigen (PSMA)
• metastatic prostate cancer
• imaging probes
• radionuclides
• Lys-urea-Glu

Article Highlights

• PSMA is a type II transmembrane protein that is overexpressed in patients with metastatic prostate cancer.

• Hydrophilic PSMA-targeted inhibitors can easily access the PSMA active site in the extracellular region.

• Lys-urea-Glu is the most common motif for developing PSMA-targeted imaging or therapeutic probes.

• Bulky moieties including metal chelators, optical dyes, and cytotoxic agents have been successfully introduced by exploiting the tunnel region of the PSMA active site.

• This review covers 32 patents published from January 2017 to June 2020, describing small molecules based on the Lys-urea-Glu or Glu-urea-Glu structures.

• Most PSMA-targeted agents described in the patents demonstrated strong PSMA-inhibitory activities in the nanomolar IC50ranges and high tumor-to-background ratio (>5) inex vivo and in vivo experiments.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Supplemental material

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Additional information

Funding

This paper was supported by the National Research Foundation of Korea (2019R1A6A1A03031807 and 2020R1A2C2005919)