Androgen Receptor-Directed Molecular Conjugates for Targeting Prostate Cancer

Abstract

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 an 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 down-regulation 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 photo-sensitizers) and selectively directs drug action toward receptor-positive PC cells.

Identification of key genes and multiple molecular pathways of metastatic process in prostate cancer

“…The androgen receptor gene is located on the X chromosome at location Xq11-12. It is well known that AR represents a vital driving force in the development and progression of prostate (Beretta & Zaffaroni, 2019) and the signaling pathway of AR plays important roles in prostate carcinogenesis and metastatic or androgen-independent progression of the disease (Tien & Sadar, 2019). In addition, Mills (2014) reported that AR involves in PCa development by affecting genomic stability and DNA repair.…”

Metabolic Plasticity in Chemotherapy Resistance

“…Chemotherapeutic drugs target a differential feature of cancer cells that help them to actively proliferate. The main types of chemotherapy agents used in the clinics are: alkylating agents and platinants (damage DNA), such as cisplatin (101); cytotoxic antibiotics (bind DNA to prevent DNA and/or RNA synthesis); inhibitors of topoisomerase (damage DNA), such as daunorubicin, doxorubicin, irinotecan and etoposide; antimetabolites (interfere with intermediary metabolism of proliferating cells), such as gemcitabine; anti-microtubule agents (target microtubules and associated proteins required in cell division), such as paclitaxel and docetaxel (102); hormonal agents (inhibit hormone synthesis or function as hormone receptor agonist/antagonist) (103), such as tamoxifen or enzalutamide; and immunotherapy (target cancer cells that express a specific antigen or boost the natural ability of T cells to fight cancer), such as trastuzumab.…”

An Overview of Next-Generation Androgen Receptor-Targeted Therapeutics in Development for the Treatment of Prostate Cancer

“…Many AR-degrading PROTACs exist, however, ARCC-4 ( 26 ) is shown here as an exemplary SARD [ 40 , 45 , 46 ]. ARCC-4 ( 26 ) in Figure 4 utilizes 3 as the AR ligand and VHL as the ubiquitin ligase, thereby targeting AR to the protease for degradation.…”