Novel PSMA-Targeting Radionuclide Peptidomimetics for Treating Prostate Cancer

Abstract

Prostate cancer is the third-most commonly diagnosed cancer and is one of the leading causes of cancer-related deaths in men worldwide. Although an armamentarium of approved drugs exists, treatment options become severely limited when resistance develops against last-line taxane chemotherapeutics. In March 2022, the FDA approved a first-in-class targeted radionuclide therapy, lutetium Lu 177 vipivotide tetraxetan (Pluvicto), for treating metastatic castration-resistant prostate cancer. The drug constitutes a prostate-specific membrane antigen-targeting peptidomimetic moiety conjugated to a radionuclide chelator via a linker. This Patent Highlight reveals the structure–activity relationship of key compounds against prostate cancer cells.

Important Compound Classes

Title

Labeled Inhibitors of Prostate Specific Membrane Antigen (PSMA), Their Use as Imaging Agents and Pharmaceutical Agents for the Treatment of Prostate Cancer

Patent Publication Number

US 2016/0228587 A1

Publication Date

August 11, 2016

Priority Application

PCT/EP2014/002808

Priority Date

October 17, 2014

Inventors

Eder, M.; Kopka, K.; Schäfer, M.; Bauder-Wüst, U.; Haberkorn, U.; Eisenhut, M.; Mier, W.; Benesova, M.

Assignee Company

Deutsches Krebsforschungszentrum, Heidelberg (Germany); Ruprecht-Karls-Universitat Heidelberg (Germany)

Disease Area

Prostate cancer

Biological Target

PSMA

Summary

Prostate cancer is the third-most commonly diagnosed cancer and is one of the leading causes of cancer-related mortality worldwide.¹ An estimated 10 million men are presently diagnosed, and more than 400,000 fatalities are recorded annually. Early-stage prostate cancer is managed by surgery and/or radiotherapy, but late-stage disease requires drug interventions comprising luteinizing hormone-releasing hormone mimetics, androgen receptor signaling inhibitors, poly-adenosine diphosphate–ribose polymerase inhibitors, and taxane chemotherapy. Unfortunately, these treatment options inevitably fail due to the emergence of drug resistance.^2,3

In March 2022, the FDA approved a new treatment modality, lutetium Lu 177 vipivotide tetraxetan (Pluvicto), for treating prostate-specific membrane antigen (PSMA)-positive metastatic castration-resistant prostate cancer (mCRPC) patients who have been treated with androgen receptor pathway inhibitors and a taxane-based chemotherapeutic.⁴ PSMA is a transmembrane glycoprotein found highly expressed on the surfaces of prostate cancer cells with expression levels increasing with cancer progression.⁴ The drug binds to PSMA via its glutamic acid–lysine peptidomimetic moiety and kills the cancer cell by radiation emitted from a radioactive lutetium ion chelated to tetraxetan conjugated to the peptidomimetic via a linker. Positive phase 3 clinical trial results involving 831 patients (NCT03511664) led to its marketing approval on March 23, 2022.⁴

Key Structures

The patent describes 18 structures with their synthetic procedures. Key exemplified structures, including Pluvicto (MB17), with in vitro IC₅₀s against human prostate cancer cells are tabulated (vide infra).

Biological Assay

IC₅₀s were determined in a cell-based assay where exemplified compounds were incubated at room temperature for 45 min on a shaker with 10⁵ LNCaP human prostate cancer cells (ATCC CRL-1740) grown in Opti-MEM media over a range of concentrations.

Biological Data

IC₅₀s of exemplified compounds against LNCaP human prostate cancer cells are summarized in the following table:

Glossary

Abbreviations

FDA

U.S. Food and Drug Administration

IC₅₀

50% inhibition concentration

LNCaP

lymph node adenocarcinoma of the prostate

mCRPC

metastatic castration-resistant prostate cancer

MEM

minimal essential medium

PSMA

prostate-specific membrane antigen

Agency for Science, Technology and Research (A*STAR), Singapore.

The author declares no competing financial interest.