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Front. Chem. | doi: 10.3389/fchem.2019.00369

Androgen receptor-directed Molecular Conjugates for Targeting Prostate Cancer

 Giovanni L. Beretta1* and Nadia Zaffaroni1*
  • 1National Tumor Institute (Italy), Italy

Due to its central role in the cellular biology of prostate cancer (PC), androgen receptor (AR) still remains an important therapeutic target for fighting this tumor. Several drugs targeting AR have been reported so far, and many new molecules are expected for the future. In spite of their antitumor efficacy, these drugs are not selective for malignant cells and are subjected to AR-mediated activation of drug resistance mechanisms that are responsible for several drawbacks, including systemic toxicity and disease recurrence and metastasis. Among the several strategies considered to overcome these drawbacks, very appealing appears the design of hybrid small-molecule conjugates targeting AR to drive drug action on receptor-positive PC cells. These compounds are designed around on a AR binder, which selectively engages AR with high potency, coupled with a moiety endowed with different pharmacological properties. In this review we focus on two classes of compounds: a) small-molecules and AR-ligand based conjugates that reduce AR expression, which allow downregulation of AR levels by activating its proteasome-mediated degradation, and b) AR-ligand-based conjugates for targeting small-molecules, in which the AR binder tethers small-molecules, including conventional antitumor drugs (e.g., cisplatin, doxorubicin, histone deacetylase inhibitors, as well as photosensitizers) and selectively directs drug action toward receptor-positive PC cells.

Keywords: prostate 
cancer, Drug Resistance, Drug conjugates, Proteolysis targeting chimera, Selective androgen receptor degraders (SARDs)

Received: 11 Mar 2019; Accepted: 06 May 2019.

Edited by:

Sanjay V. Malhotra, Stanford University, United States

Reviewed by:

Marco Tutone, University of Palermo, Italy
Carlotta Granchi, University of Pisa, Italy  

Copyright: © 2019 Beretta and Zaffaroni. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence:
PhD. Giovanni L. Beretta, National Tumor Institute (Italy), Milan, 20133, Lombardy, Italy,
PhD. Nadia Zaffaroni, National Tumor Institute (Italy), Milan, 20133, Lombardy, Italy,