Targeting prostate cancer with compounds possessing dual activity as androgen receptor antagonists and HDAC6 inhibitors

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• 作者：Pradeep S. Jadhavar^a ; Sreekanth A. Ramachandran^a ; Eduardo Riquelme^b ; Ashu Gupta^a ; Kevin P. Quinn^c ; Devleena Shivakumar^d ; Soumya Ray^d ; Dnyaneshwar Zende^a ; Anjan K. Nayak^a ; Sandeep K. Miglani^a ; Balaji D. Sathe^a ; Mohd. Raja^a ; Olivia Farias^b ; Ivan Alfaro^b ; Sebastiá ; n Belmar^b ; Javier Guerrero^b ; Sebastiá ; n Bernales^c ; Sarvajit Chakravarty^c ; David T. Hung^c ; Jeffrey N. Lindquist^c ; ^{jeffrey.lindquist@medivation.com" class="auth_mail" title="E-mail the corresponding author} ; Roopa Rai^c ; ^{roopa.rai@hotmail.com" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Prostate cancer ; Enzalutamide ; HDAC6 inhibitor ; Androgen receptor (AR) antagonist ; Induced fit docking (IFD)
• 刊名：Bioorganic & Medicinal Chemistry Letters
• 出版年：2016
• 出版时间：1 November 2016
• 年：2016
• 卷：26
• 期：21
• 页码：5222-5228
• 全文大小：1346 K

文摘

While enzalutamide and abiraterone are approved for treatment of metastatic castration-resistant prostate cancer (mCRPC), approximately 20–40% of patients have no response to these agents. It has been stipulated that the lack of response and the development of secondary resistance to these drugs may be due to the presence of AR splice variants. HDAC6 has a role in regulating the androgen receptor (AR) by modulating heat shock protein 90 (Hsp90) acetylation, which controls the nuclear localization and activation of the AR in androgen-dependent and independent scenarios. With dual-acting AR–HDAC6 inhibitors it should be possible to target patients who don’t respond to enzalutamide. Herein, we describe the design, synthesis and biological evaluation of dual-acting compounds which target AR and are also specific towards HDAC6. Our efforts led to compound 10 which was found to have potent dual activity (HDAC6 IC₅₀ = 0.0356 μM and AR binding IC₅₀ = <0.03 μM). Compound 10 was further evaluated for antagonist and other cell-based activities, in vitro stability and pharmacokinetics.