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

Abstract

Androgen receptor (AR) plays a vital role in prostate cancer (PCa), including castration-resistant PCa, by retaining AR signalling. Androgen deprivation treatment (ADT) has been the standard treatment in the past decades. A great number of AR antagonists initially had been found effective in tumour remission; however, most PCa relapsed that caused by pre-translational resistance such as AR mutations to turn antagonist into agonist, and AR variants to bypass the androgen binding. Recently, several alternative therapeutic choices have been proposed. Among them, proteolysis targeting chimera (PROTAC) acts different from traditional drugs that usually function as inhibitors or antagonists, and it degrades oncogenic protein and does not disrupt the transcription of an oncogene. This review first discussed some essential mechanisms of ADT resistance, and then introduced the application of AR-targeted PROTAC in PCa cells, as well as other AR-targeted therapeutic choices.

Androgen receptor suppresses lung cancer invasion and increases cisplatin response via decreasing TPD52 expression

“…Generally, AR belongs to the nuclear receptor subfamily, which encompasses other receptors such as estrogen receptor (ER), progesterone receptor (PR), and glucocorticoid receptor (GR) [10]. The AR gene is located on the X chromosome at position q11-12 and consists of eight exons, encoding a protein with four functional domains [11]. It is gradually acknowledged that AR plays various roles in the development of prostate cancer, bladder cancer, kidney cancer, liver cancer, etc [12][13][14][15][16][17].…”

PROTACs: A novel strategy for cancer drug discovery and development

“…A typical PROTAC degrader consists of three components: the target‐binding small molecule ligand (protein of interest, POI), the E3 ligase ligand and the appropriate linker that connects the two components (Figure 1). 50,66–73 E3 ligases and the corresponding ligands are important as the driving force of protein degradation 74–91 . Good drug‐like small‐molecule ligands for a E3 ligase system are still limited 92–97 .…”

“… 50 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 E3 ligases and the corresponding ligands are important as the driving force of protein degradation. 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 , 86 , 87 , 88 , 89 , 90 , 91 Good drug‐like small‐molecule ligands for a E3 ligase system are still limited. 92 , 93 , 94 , 95 , 96 , 97 Although more than 600 E3 ligases are encoded by human genome, only less than 10 E3 ligases were developed as ligands for the development of PROTAC degraders, including von Hippel‐Lindau (VHL), cereblon (CRBN), mouse double minute 2 (MDM2), cellular IAP1 (cIAP1), Kelch‐like ECH‐associated protein‐1 (KEAP1), DDB1‐cullin 4‐associated factor (DCAF), RING finger protein (RNF), aryl hydrocarbon receptor (AHR), and others (Figure 1 ).…”