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Pharmacological Characterization of a Novel Bifunctional Aldo-Keto Reductase 1C3 Inhibitor and Androgen Receptor Antagonist

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Final rept. 1 Jun 2013

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The development of advanced prostate cancer APC after androgen deprivation therapy is characterized by reactivation of androgen receptor AR signaling within the tumor despite castrate levels of circulating androgens. This is caused by elevated intratumoral androgen biosynthesis andor aberrant androgen receptor activation. Targeting both mechanisms of recurrence can provide superior therapeutic benefit relative to targeting either mechanism alone. Aldo-keto reductase 1C3 AKR1C3 is highly upregulated in APC and is localized within the tumor. We report continuing pharmacological characterization of BMT 4-158, a bifunctional AKR1C3 inhibitor and AR antagonist. BMT4-158 competes with androgens for binding to the AR ligand binding domain LBD leading to reduced AR activation. It also blocks the androgen induced nuclear translocation that is essential for AR signaling. BMT4-158 is active in cellular context of both wild type and mutated AR. It reduces AR levels and inhibits the androgen dependent gene expression of PSA in parental LNCaP AKR1C3 null cells and LNCaP cells stably expressing AKR1C3. Bifunctional compounds like BMT4-158 have the potential to be superior agents for treatment of APC and may also surmount resistance to existing therapeutic agents like Abiraterone Abi and MDV3100 that target a single pathway.

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  • Anatomy and Physiology
  • Medicine and Medical Research

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