Development of an Androgen Receptor Inhibitor Targeting the N-Terminal Domain of Androgen Receptor for Treatment of Castration Resistant Prostate Cancer

Abstract

Prostate cancer patients undergoing androgen deprivation therapy almost invariably develop castration-resistant prostate cancer. Resistance can occur when mutations in the androgen receptor (AR) render anti-androgen drugs ineffective or through the expression of constitutively active splice variants lacking the androgen binding domain entirely (e.g., ARV7). In this study, we are reporting the discovery of a novel AR-NTD covalent inhibitor 1-chloro-3-[(5-([(2S)-3-chloro-2-hydroxypropyl]amino)naphthalen-1-yl)amino]propan-2-ol (VPC-220010) targeting the AR-N-terminal Domain (AR-NTD). VPC-220010 inhibits AR-mediated transcription of full length and truncated variant ARV7, downregulates AR response genes, and selectively reduces the growth of both full-length AR- and truncated AR-dependent prostate cancer cell lines. We show that VPC-220010 disrupts interactions between AR and known coactivators and coregulatory proteins, such as CHD4, FOXA1, ZMIZ1, and several SWI/SNF complex proteins. Taken together, our data suggest that VPC-220010 is a promising small molecule that can be further optimized into effective AR-NTD inhibitor for the treatment of CRPC.

DisProt in 2022: improved quality and accessibility of protein intrinsic disorder annotation

“…Recent successes in the field, i.e. targeting c-Myc ( 25 ), androgen receptor ( 26 ) or alpha-synuclein ( 27 ), encourage us to adhere to this ambition. The concept of liquid-liquid phase separation (LLPS) leading to the formation of membraneless organelles (MLOs) raises hope that IDP/IDR function and therapeutic targeting can now be approached from a novel angle ( 28 , 29 ).…”

Topological dynamics of an intrinsically disordered N‐terminal domain of the human androgen receptor

“…4 However, additional studies show the AR-NTD can also fold in functional state, as truncated forms of AR, devoid of the LBD, act as constitutively fully active form, 5 suggesting a central role of the NTD as a transcriptional driver. 6,7 This makes the NTD an interesting target for drug development, [8][9][10] however the absence of high-resolution information has challenged this development.…”

Hybrid Androgen Receptor Inhibitors Outperform Enzalutamide and EPI‐001 in in vitro Models of Prostate Cancer Drug Resistance

“…To evaluate whether the cell toxicity was AR mediated, we performed complementary cytotoxicity studies on PC‐3 cells. PC‐3 cells are metastatic adenocarcinoma cells that express very low levels of AR [31] and therefore both enzalutamide and EPI‐001 are not toxic at concentrations lower than 100 μM [32] . Compounds 9 a – 9 e were therefore expected to not display any significant toxicity towards the PC‐3 cell line.…”

“…Enzalutamide acted as a positive control at a concentration of 5 μM, while EPI-001 was not able to inhibit the KLK3 gene transcription at the tested concentration, in accordance with previous findings. [32] Compound 9 b was able to significantly inhibit the KLK3 gene transcription at the tested concentrations (Figure 4b). While compound 9e failed to induce a statistically significant change in KLK3 gene expression (p = 0.1186), compound 9 b was able to cause a significant change (p = 0.0397).…”