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Article Dans Une Revue Cancers Année : 2021

Development of an androgen receptor inhibitor targeting the n-terminal domain of androgen receptor for treatment of castration resistant prostate cancer

Résumé

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.
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Dates et versions

hal-03944714 , version 1 (18-01-2023)

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Paternité - CC BY 4.0

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Fuqiang Ban, Eric Leblanc, Ayse Derya Cavga, Chia-Chi Flora Huang, Mark R. Flory, et al.. Development of an androgen receptor inhibitor targeting the n-terminal domain of androgen receptor for treatment of castration resistant prostate cancer. Cancers, 2021, Cancers, 13 (14), pp.3488. ⟨10.3390/cancers13143488⟩. ⟨hal-03944714⟩

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