Novel small molecule guanidine Sigma1 inhibitors for advanced prostate cancer

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:27

Article

Salvino, Joseph M.¹  Srikanth, Yellamelli V. V.¹  Lou, Rongliang²  Oyer, Halley M.¹  Chen, Nan¹  Kim, Felix J.¹ 

[1] Drexel Univ, Coll Med, Dept Physiol & Pharmacol, 245 N 15th St, Philadelphia, PA 19102 USA

[2] AstaTech Inc, Keystone Business Pk,2525 Pearl Buck Rd, Bristol, PA 19007 USA

关键词: Sigma1;    Sigma-1 receptor;    Sigma-1 chaperone;    Prostate cancer;    Guanidine;    Small molecule inhibitor;   

DOI  :  10.1016/j.bmcl.2017.03.030

来源: Elsevier

【 摘 要 】

Prostate cancer is the most frequently diagnosed malignancy and the leading cause of cancer related death in men. First line therapy for disseminated disease relies on androgen deprivation, leveraging the addiction of these tumors on androgens for both growth and survival. Treatment typically involves antagonizing the androgen receptor (AR) or blocking the synthesis of androgens. Recurrence is common and within 2-3 years patients develop castration resistant tumors that become unresponsive to AR-axis targeted therapies. In order to provide a more effective treatment, we are utilizing an approach that targets a key scaffolding protein, Sigma1 (also known as sigma-1 receptor), a unique 26-kilodalton integral membrane protein that is critical in stabilizing the AR. Herein we report on a new series of Sigmal compounds for lead optimization derived from a hybrid pharmacophore approach. (C) 2017 Elsevier Ltd. All rights reserved.

【 授权许可】

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