BAG1L: a promising therapeutic target for androgen receptor-dependent prostate cancer

Abstract

Androgens are important determinants of normal and malignant prostate growth. They function by binding to the C-terminal ligand-binding domain (LBD) of the androgen receptor (AR). All clinically approved AR-targeting antiandrogens for prostate cancer therapy function by competing with endogenous androgens. Despite initial robust responses to androgen deprivation therapy, nearly all patients with advanced prostate cancer relapse with lethal castration-resistant prostate cancer (CRPC). Progression to CRPC is associated with ongoing AR signaling, which in part, is due to the expression of constitutively active AR splice variants that contain the N-terminus of the receptor but lack the C-terminus. Currently, there are no approved therapies specifically targeting the AR N-terminus. Current pharmacologic targeting strategies for inhibiting the AR N-terminal region have proven difficult, due to its intrinsically unstructured nature and lack of enzymatic activity. An alternative approach is to target key molecules such as the cochaperone BAG1L that bind to and enhance the activity of the AR AF1. Here, we review recent literature that suggest Bag-1L is a promising target for AR-positive prostate cancer.

A chemical probe for BAG1 targets androgen receptor-positive prostate cancer through oxidative stress signaling pathway

“…We have previously reported that BAG1L uses its conserved BAG domain to interact with the AR N-terminal domain (NTD) to enhance its activity ( Cato et al., 2017 ; Shatkina et al., 2003 ). Because the AR NTD is an important domain for the transactivation function of the AR ( Yu et al., 2020 ) and the AR a key driver of prostate cancer, small molecules targeting the BAG-AR NTD interaction interface would inhibit AR activity and function as prostate cancer therapeutics ( Lee et al., 2019 ).…”

Identification and Characterization of Alternatively Spliced Transcript Isoforms of IRX4 in Prostate Cancer

“…Androgen deprivation therapy (ADT) has been the mainstay of management for advanced PCa. Despite the initial strong responses to androgen deprivation therapy, the majority of patients with advanced PCa relapse with fatal castration-resistant PCa (CRPC) [ 60 ]. According to our data, IRX4 and its isoforms are differentially expressed depending on the cell lines’ androgen responsiveness.…”

Mechanistic Insights into the Allosteric Inhibition of Androgen Receptors by Binding Function 3 Antagonists from an Integrated Molecular Modeling Study

“…The AR-BF3 targeting compounds containing a benzimidazole or benzindole scaffold were collected from Cherkasov et al's publications 28,30 and were further classified into five categories according to their substitution groups (Table S1). Representative compounds of each series (15,21,24,32,38,43,47,52,54, and 12m) were selected for the following computational studies. Among these compounds, the ternary crystal structure of 32 bound AR complexed with an endogenous agonist testosterone (TES) (AR/TES/32) (PDB ID: 4HLW) was used as the template to model the binding poses of the other chosen derivatives (15, 21, 24, 38, 43, 47, 52, 54, and 12m) in the BF3 site of AR/TES.…”