Discovery of 2-methyl-1-{1-[(5-methyl-1H-indol-2-yl)carbonyl]piperidin-4-yl}propan-2-ol: A novel, potent and selective type 5 17β-hydroxysteroid dehydrogenase inhibitor

Watanabe, Kazushi; Kakefuda, Akio; Yasuda, Minoru; Enjo, Kentaro; Kikuchi, Aya; Furutani, Takashi; Naritomi, Yoichi; Otsuka, Yukio; Okada, Minoru; Ohta, Mitsuaki

doi:10.1016/j.bmc.2013.06.025

Cited by 8 publications

(8 citation statements)

References 18 publications

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“…17-HSD5 inhibition assays were conducted as described previously (Watanabe et al, 2013). Briefly, 9,10-phenanthrenequinone (9,10-PQ) was used as the substrate and the oxidation of the cofactor NADPH was measured by monitoring the change in absorbance at 340 nm.…”

Section: Enzyme Assaymentioning

confidence: 99%

“…Compound 5 was identified by Astellas Pharma (Watanabe et al, 2013). After HTS, compound 5 was focused on owing to its unique chemical structure among 17-HSD5 inhibitors.…”

Section: Crystal Structure Of 17b-hsd5 Complexed With Compound 5 and mentioning

confidence: 99%

“…Astellas Pharma conducted HTS using a 17-HSD5 enzyme assay against an in-house chemical library and synthesized potent noncarboxylate inhibitors of 17-HSD5 (Watanabe et al, 2013). Although the details have not been reported, structurally diverse inhibitors, including noncarboxylate compounds, were identified from HTS.…”

Section: Introductionmentioning

confidence: 99%

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Structures of complexes of type 5 17β-hydroxysteroid dehydrogenase with structurally diverse inhibitors: insights into the conformational changes upon inhibitor binding

Amano

Yamaguchi

Niimi

et al. 2015

Acta Cryst D Biol Crystallogr

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Type 5 17β-hydroxysteroid dehydrogenase (17β-HSD5) is an aldo-keto reductase expressed in the human prostate which catalyzes the conversion of androstenedione to testosterone. Testosterone is converted to 5α-dihydrotestosterone, which is present at high concentrations in patients with castration-resistant prostate cancer (CRPC). Inhibition of 17β-HSD5 is therefore considered to be a promising therapy for treating CRPC. In the present study, crystal structures of complexes of 17β-HSD5 with structurally diverse inhibitors derived from high-throughput screening were determined. In the structures of the complexes, various functional groups, including amide, nitro, pyrazole and hydroxyl groups, form hydrogen bonds to the catalytic residues His117 and Tyr55. In addition, major conformational changes of 17β-HSD5 were observed following the binding of the structurally diverse inhibitors. These results demonstrate interactions between 17β-HSD5 and inhibitors at the atomic level and enable structure-based drug design for anti-CRPC therapy.

show abstract

Section: Enzyme Assaymentioning

confidence: 99%

“…Compound 5 was identified by Astellas Pharma (Watanabe et al, 2013). After HTS, compound 5 was focused on owing to its unique chemical structure among 17-HSD5 inhibitors.…”

Section: Crystal Structure Of 17b-hsd5 Complexed With Compound 5 and mentioning

confidence: 99%

See 1 more Smart Citation

Structures of complexes of type 5 17β-hydroxysteroid dehydrogenase with structurally diverse inhibitors: insights into the conformational changes upon inhibitor binding

Amano

Yamaguchi

Niimi

et al. 2015

Acta Cryst D Biol Crystallogr

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“…This reaction is catalyzed by aldo-keto reductase family 1 member 3 (AKR1C3) (also known as HSD17β) [60]. AKR1C3 inhibitors are currently under development [61]. A second mechanism to block androgen is to target 5-α reductase with finasteride and dutasteride, which blocks the intracellular conversion of testosterone to its higher binding affinity derivative DHT [62, 63].…”

Section: Androgen Receptor Antagonistsmentioning

confidence: 99%

The importance of non-nuclear AR signaling in prostate cancer progression and therapeutic resistance

Zarif

Miranti

2016

Cellular Signalling

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The androgen receptor (AR) remains the major oncogenic driver of prostate cancer, as evidenced by the efficacy of androgen deprivation therapy (ADT) in naïve patients, and the continued effectiveness of second generation ADTs in castration resistant disease. However, current ADTs are limited to interfering with AR ligand binding, either through suppression of androgen production or the use of competitive antagonists. Recent studies demonstrate 1) the expression of constitutively active AR splice variants that no longer depend on androgen, and 2) the ability of AR to signal in the cytoplasm independently of its transcriptional activity (non-genomic); thus highlighting the need to consider other ways to target AR. Herein, we review canonical AR signaling, but focus on AR non-genomic signaling, some of its downstream targets and how these effectors contribute to prostate cancer cell behavior. The goals of this review are to 1) re-highlight the continued importance of AR in prostate cancer as the primary driver, 2) discuss the limitations in continuing to use ligand binding as the sole targeting mechanism, 3) discuss the implications of AR non-genomic signaling in cancer progression and therapeutic resistance, and 4) address the need to consider non-genomic AR signaling mechanisms and pathways as a viable targeting strategy in combination with current therapies.

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“…These findings have led to a spectrum of AKR1C3 inhibitors being developed both in academia and in industry. Astellas Pharmaceuticals and GTx have both developed AKRC13 inhibitors (Astellas Pharmaceuticals 2013, Watanabe et al . 2013, Yepuru et al .…”

Section: Enzyme Targets and Their Inhibitionmentioning

confidence: 99%

Androgen biosynthesis in castration-resistant prostate cancer

Penning¹

2014

Endocrine-Related Cancer

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Prostate cancer is the second leading cause of death in adult males in the USA. Recent advances have revealed that the fatal form of this cancer, known as castration-resistant prostate cancer (CRPC), remains hormonally driven despite castrate levels of circulating androgens. CRPC arises as the tumor undergoes adaptation to low levels of androgens by either synthesizing its own androgens (intratumoral androgens) or altering the androgen receptor (AR). This article reviews the major routes to testosterone and dihydrotestosterone synthesis in CRPC cells and examines the enzyme targets and progress in the development of isoform-specific inhibitors that could block intratumoral androgen biosynthesis. Because redundancy exists in these pathways, it is likely that inhibition of a single pathway will lead to upregulation of another so that drug resistance would be anticipated. Drugs that target multiple pathways or bifunctional agents that block intratumoral androgen biosynthesis and antagonize the AR offer the most promise. Optimal use of enzyme inhibitors or AR antagonists to ensure maximal benefits to CRPC patients will also require application of precision molecular medicine to determine whether a tumor in a particular patient will be responsive to these treatments either alone or in combination.

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Discovery of 2-methyl-1-{1-[(5-methyl-1H-indol-2-yl)carbonyl]piperidin-4-yl}propan-2-ol: A novel, potent and selective type 5 17β-hydroxysteroid dehydrogenase inhibitor

Cited by 8 publications

References 18 publications

Structures of complexes of type 5 17β-hydroxysteroid dehydrogenase with structurally diverse inhibitors: insights into the conformational changes upon inhibitor binding

Structures of complexes of type 5 17β-hydroxysteroid dehydrogenase with structurally diverse inhibitors: insights into the conformational changes upon inhibitor binding

The importance of non-nuclear AR signaling in prostate cancer progression and therapeutic resistance

Androgen biosynthesis in castration-resistant prostate cancer

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