4.7 Article

Selectively targeting the dimerization interface of human androgen receptor with small-molecules to treat castration-resistant prostate cancer

期刊

CANCER LETTERS
卷 437, 期 -, 页码 35-43

出版社

ELSEVIER IRELAND LTD
DOI: 10.1016/j.canlet.2018.08.016

关键词

Androgen receptor; Prostate cancer; Dimerization; Small molecule inhibitor

类别

资金

  1. Canadian Institutes of Health Research (CIHR) [272111]
  2. Prostate Cancer Canada-Translational Acceleration Grant (PCC-TAG) [TAG2014-05]
  3. Terry Fox New Frontiers Program Project grant (TFRI) [1062]

向作者/读者索取更多资源

Prostate cancer (PCa) is a leading cause of death for men in North America. The androgen receptor (AR) - a hormone inducible transcription factor - drives expression of tumor promoting genes and represents an important therapeutic target in PCa. The AR is activated by steroid recruitment to its ligand binding domain (LBD), followed by receptor nuclear translocation and dimerization via the DNA binding domain (DBD). Clinically used small molecules interfere with steroid recruitment and prevent AR-driven tumor growth, but are rendered ineffective by emergence of LBD mutations or expression of constitutively active variants, such as ARV7, that lack the LBD. Both drug-resistance mechanisms confound treatment of this 'castration resistant' stage of PCa (CRPC), characterized by return of AR signalling. Here, we employ computer-aided drug-design to develop small molecules that block the AR-DBD dimerization interface, an attractive target given its role in AR activation and independence from the LBD. Virtual screening on the AR-DBD structure led to development of prototypical compounds that block AR dimerization, inhibiting AR-transcriptional activity through a LBD-independent mechanism. Such inhibitors may potentially circumvent AR-dependent resistance mechanisms and directly target CRPC tumor growth.

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