Second generation androgen receptor antagonists and challenges in prostate cancer treatment

Abstract

Prostate cancer is a hormone-dependent malignancy, whose onset and progression are closely related to the activity of the androgen receptor (AR) signaling pathway. Due to this critical role of AR signaling in driving prostate cancer, therapy targeting the AR pathway has been the mainstay strategy for metastatic prostate cancer treatment. The utility of these agents has expanded with the emergence of second-generation AR antagonists, which began with the approval of enzalutamide in 2012 by the United States Food and Drug Administration (FDA). Together with apalutamide and darolutamide, which were approved in 2018 and 2019, respectively, these agents have improved the survival of patients with prostate cancer, with applications for both androgen-dependent and castration-resistant disease. While patients receiving these drugs receive a benefit in the form of prolonged survival, they are not cured and ultimately progress to lethal neuroendocrine prostate cancer (NEPC). Here we summarize the current state of AR antagonist development and highlight the emerging challenges of their clinical application and the potential resistance mechanisms, which might be addressed by combination therapies or the development of novel AR-targeted therapies.

Cheminformatic Analysis and Machine Learning Modeling to Investigate Androgen Receptor Antagonists to Combat Prostate Cancer

“…With the use of first-generation antagonists, patients eventually proceed to CRPC. Second-generation antagonists (enzalutamide, 2012; apalutamide, 2018; and darolutamide, 2019) have been approved since 2012, and they have much more potent binding affinities with AR than the first-generation antagonists. , However, there are two challenges for second-generation antagonists: first, enzalutamide and apalutamide have off-target effects on the GABA-a receptors in the central nervous system and tend to induce seizures in a portion of patients. Second, like the first generation, they inevitably induce drug resistance in the long term.…”

“…Therefore, they are gradually replaced by the second-generation antagonists represented by enzalutamide, apalutamide, and darolutamide. In addition to the competitive inhibition of androgen-AR binding, second-generation antagonists also inhibit the AR translocation from cytoplasm to cell nucleus, the coactivator recruitment, and the AR-DNA binding . Although the second-generation antagonists display advantages over the first-generation antagonists, they have inevitably induced AR-resistant mutations that can render these drugs partial or mixed agonists for AR …”

The androgen receptor-targeted proteolysis targeting chimera and other alternative therapeutic choices in overcoming the resistance to androgen deprivation treatment in prostate cancer

“…On the other hand, the PDX without AR gene amplification was sensitive to AR antagonists [ 17 ]. Several novel AR antagonists have been synthesized and recently tested in clinical trials, for example, Proxalutamide, TQB3720, and SHR3680 [ 18 ] (Table 1 ).…”

Second generation androgen receptor antagonist, TQB3720 abrogates prostate cancer growth via AR/GPX4 axis activated ferroptosis

“…Thus, the scientists develop the second-generation AR antagonists to address these shortcomings. Nowadays, TQB3720 has been considered as a second-generation AR antagonist (Chen et al, 2022). However, the molecular mechanisms of TQB3720 in PCa remains unexplored completely.…”

“…The induction of ferroptosis in tumor cells is expected to address drug resistance to conventional radiotherapy (Zhang et al, 2019;Zhou et al, 2019). TQB3720, a second-generation AR antagonist which is developed by Chia Tai Tianqing Pharmaceutical Group Co., Ltd., competes for binding to AR and causes its loss of function (Chen et al, 2022). Most importantly, this chemical is under the evaluation of the tolerance and pharmacokinetics in clinical trial phase 1 stage (ClinicalTrials.gov Identifier: NCT04853498).…”