1. Targeting prostate cancer with compounds possessing dual activity as androgen receptor antagonists and HDAC6 inhibitors.
- Author
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Jadhavar PS, Ramachandran SA, Riquelme E, Gupta A, Quinn KP, Shivakumar D, Ray S, Zende D, Nayak AK, Miglani SK, Sathe BD, Raja M, Farias O, Alfaro I, Belmar S, Guerrero J, Bernales S, Chakravarty S, Hung DT, Lindquist JN, and Rai R
- Subjects
- Androgen Antagonists chemistry, Androgen Antagonists pharmacokinetics, Animals, Cell Line, Tumor, Crystallography, X-Ray, HSP90 Heat-Shock Proteins metabolism, Histone Deacetylase 6, Histone Deacetylase Inhibitors chemistry, Histone Deacetylase Inhibitors pharmacokinetics, Humans, Male, Mice, Models, Molecular, Androgen Antagonists pharmacology, Histone Deacetylase Inhibitors pharmacology, Histone Deacetylases drug effects, Prostatic Neoplasms pathology
- Abstract
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 IC
50 =0.0356μM and AR binding IC50 =<0.03μM). Compound 10 was further evaluated for antagonist and other cell-based activities, in vitro stability and pharmacokinetics., (Copyright © 2016 Elsevier Ltd. All rights reserved.)- Published
- 2016
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