In vitro and in vivo characterisation of ASP9521: a novel, selective, orally bioavailable inhibitor of 17β-hydroxysteroid dehydrogenase type 5 (17βHSD5; AKR1C3)

Kikuchi, Aya; Furutani, Takashi; Azami, Hidenori; Watanabe, Kazushi; Niimi, Tatsuya; Kamiyama, Yoshiteru; Kuromitsu, Sadao; Baskin-Bey, Edwina S.; Heeringa, Marten; Ouatas, Taoufik; Enjo, Kentaro

doi:10.1007/s10637-014-0130-5

Cited by 49 publications

(57 citation statements)

References 33 publications

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“…From the same high-throughput screen that enabled the discovery of SN33638 also came Figure 9) and GTx-560 (27), respectively [66,67] . However, only ASP9521 has so far been the subject of clinical evaluation.…”

Section: Heinrich Et Almentioning

confidence: 99%

Androgen-AR axis in primary and metastatic prostate cancer: chasing steroidogenic enzymes for therapeutic intervention

Pippione¹,

Boschi²,

Pors³

et al. 2017

JCMT

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Androgens play an important role in prostate cancer (PCa) development and progression. Although androgen deprivation therapy remains the front-line treatment for advanced prostate cancer, patients eventually relapse with the lethal form of the disease. The prostate tumor microenvironment is characterised by elevated tissue androgens that are capable of activating the androgen receptor (AR). Inhibiting the steroidogenic enzymes that play vital roles in the biosynthesis of testosterone (T) and dihydrotestosterone (DHT) seems to be an attractive strategy for PCa therapies. Emerging data suggest a role for the enzymes mediating pre-receptor control of T and DHT biosynthesis by alternative pathways in controlling intratumoral androgen levels, and thereby influencing PCa progression. This supports the idea for the development of multi-targeting strategies, involving both dual and multiple inhibitors of androgen-metabolising enzymes that are able to affect androgen synthesis and signalling at different points in the biosynthesis. In this review, we will focus on CYP17A1, AKR1C3, HSD17B3 and SRD5A, as these enzymes play essential roles in all the three androgenic pathways. We will review also the AR as an additional target for the design of bifunctional drugs. Targeting intracrine androgens and AKR1C3 have potential to overcome enzalutamide and abiraterone resistance and improve survival of advanced prostate cancer patients.

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Section: Heinrich Et Almentioning

confidence: 99%

Androgen-AR axis in primary and metastatic prostate cancer: chasing steroidogenic enzymes for therapeutic intervention

Pippione¹,

Boschi²,

Pors³

et al. 2017

JCMT

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show abstract

“…The growth of these tumors could be determined by the adaptive changes of androgen receptors (AR) such as amplifications or mutations, which have been previously described [2][3][4][5] . However, most prostate cancers are produced in an androgen-dependent manner, and the presence of intraprostatic dihydrotestosterone (DHT) could stimulate AR signaling, since this steroid is only reduced by close to 60% 4,6 with medical castration using GnRH analogues.…”

Section: Introductionmentioning

confidence: 99%

“…These androgens are also present in the plasma of cancer patients under androgen ablation therapies 5 . Therefore, the synthesis of DHT from DHEA and 4-dione is possible, since the enzymes involved in this pathway are increased in the prostates of these patients [2][3][4][5] . The enzyme 17b-HSD type 5 (17b-HSD5) is well characterized in human prostate tissues, and contributes to local androgen formation 7,8 .…”

Section: Introductionmentioning

confidence: 99%

“…The enzyme 17b-HSD type 5 (17b-HSD5) is well characterized in human prostate tissues, and contributes to local androgen formation 7,8 . The gene that encodes 17b-HSD5 has been identified in bands 10 p15 and p14 of human chromosome 13 from prostate cells and its mRNA is over-expressed in prostate cancer tissue (77%) [5][6][7][8] . Since this enzyme is produced locally in prostatic cancer tumors, it must be considered as a therapeutic target for this illness 9 .…”

Section: Introductionmentioning

confidence: 99%

“…During the conversion of 4-dione to T (Figure 1), conformational changes of 17b-HSD5 have been observed by X-ray analysis 8 . This fact has inspired researchers to design new drugs intended to inhibit the activity of this enzyme 5,7,10,11 . Studies carried out with the prostate cancer cell lines DU-145, PC-3 and LNCaP [3][4][5][6] showed increased reductive activity for 17b-HSD5 in these cell lines 9 .…”

Section: Introductionmentioning

confidence: 99%

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Biological activity of pyrazole and imidazole-dehydroepiandrosterone derivatives on the activity of 17β-hydroxysteroid dehydrogenase

Cabeza

Posada

Sánchez-Márquez

et al. 2015

Journal of Enzyme Inhibition and Medicinal Chemistry

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The enzyme type 5 17b-hydroxysteroid dehydrogenase 5 (17b-HSD5) catalyzes the transformation of androstenedione (4-dione) to testosterone (T) in the prostate. This metabolic pathway remains active in cancer patients receiving androgen deprivation therapy. Since physicians seek to develop advantageous and better new treatments to increase the average survival of these patients, we synthesized several different dehydroepiandrosterone derivatives. These compounds have a pyrazole or imidazole function at C-17 and an ester moiety at C-3 and were studied as inhibitors of 17b-HSD5. The kinetic parameters of this enzyme were determined for use in inhibition assays. Their pharmacological effect was also determined on gonadectomized hamsters treated with D 4 -androstenedione (4-dione) or testosterone (T) and/or the novel compounds. The results indicated that the incorporation of a heterocycle at C-17 induced strong 17b-HSD5 inhibition. These derivatives decreased flank organ diameter and prostate weight in castrated hamsters treated with T or 4-dione. Inhibition of 17b-HSD5 by these compounds could have therapeutic potential for the treatment of prostate cancer and benign prostatic hyperplasia.

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Design, Synthesis and Cytotoxicity Evaluation of Novel Indole Derivatives Containing Benzoic Acid Group as Potential AKR1C3 Inhibitors

Sun

Zhou

Zhuo

et al. 2020

Chemistry & Biodiversity

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Castration-resistant prostate cancer (CRPC) is a fatal, metastatic form of prostate cancer, characterized by reactivation of the androgen axis. Aldo-keto reductase 1C3 (AKR1C3) converts androstenedione (AD) and 5αandrostanedione to testosterone (T) and 5α-dihydrotestosterone (DHT), respectively. In CRPC, AKR1C3 is upregulated and implicated in drug resistance and has been regarded as a potential therapeutic target. Here we examined a series of indole derivatives containing benzoic acid or phenylhydroxamic acid and found that 4-({3-[(3,4,5-trimethoxyphenyl)sulfanyl]-1H-indol-1-yl}methyl)benzoic acid (3e) and N-hydroxy-4-({3-[(3,4,5-trimethoxyphenyl)sulfanyl]-1H-indol-1-yl}methyl)benzamide (3q) inhibited 22Rv1 cell proliferation with IC 50 values of 6.37 μM and 2.72 μM, respectively. In enzymatic assay, compounds 3e and 3q exhibited potent inhibitory effect against AKR1C3 (IC 50 = 0.26 and 2.39 μM, respectively). These results indicated that compounds 3e and 3q might be useful leads for further investigation of more potential AKR1C3 inhibitors used for CRPC.

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In vitro and in vivo characterisation of ASP9521: a novel, selective, orally bioavailable inhibitor of 17β-hydroxysteroid dehydrogenase type 5 (17βHSD5; AKR1C3)

Cited by 49 publications

References 33 publications

Androgen-AR axis in primary and metastatic prostate cancer: chasing steroidogenic enzymes for therapeutic intervention

Androgen-AR axis in primary and metastatic prostate cancer: chasing steroidogenic enzymes for therapeutic intervention

Biological activity of pyrazole and imidazole-dehydroepiandrosterone derivatives on the activity of 17β-hydroxysteroid dehydrogenase

Design, Synthesis and Cytotoxicity Evaluation of Novel Indole Derivatives Containing Benzoic Acid Group as Potential AKR1C3 Inhibitors

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