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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)
Summary Background Aldo-keto reductase 1C3 [AKR1C3;17β-hydroxysteroid dehydrogenase type 5 (17βHSD5)], plays a crucial role in persistent production of androgens despite castration, by catalysing conversion of the adrenal androgens dehydroepiandrosterone and androstenedione (AD) into androstenediol...
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Published in: | Investigational new drugs 2014-10, Vol.32 (5), p.860-870 |
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creator | Kikuchi, Aya Furutani, Takashi Azami, Hidenori Watanabe, Kazushi Niimi, Tatsuya Kamiyama, Yoshiteru Kuromitsu, Sadao Baskin-Bey, Edwina Heeringa, Marten Ouatas, Taoufik Enjo, Kentaro |
description | Summary
Background
Aldo-keto reductase 1C3 [AKR1C3;17β-hydroxysteroid dehydrogenase type 5 (17βHSD5)], plays a crucial role in persistent production of androgens despite castration, by catalysing conversion of the adrenal androgens dehydroepiandrosterone and androstenedione (AD) into androstenediol and testosterone (T). Hence, AKR1C3 is a promising therapeutic target in castration-resistant prostate cancer, as combination of an AKR1C3 inhibitor and a gonadotropin-releasing hormone analogue may lead to complete androgen blockade. This study describes the preclinical characterisation of the novel AKR1C3 inhibitor ASP9521.
Methods
The inhibitory effect of ASP9521 on AKR1C3-mediated conversion from AD into T was evaluated both in vitro and in vivo, using CWR22R xenografted mice. The effect of ASP9521 on PSA production and cell proliferation was tested using LNCaP cells stably expressing human AKR1C3 (LNCaP-AKR1C3). Pharmacokinetics of ASP9521 were studied in rats, dogs and cynomolgus monkeys.
Results
ASP9521 inhibited conversion of AD into T by recombinant human or cynomolgus monkey AKR1C3 in a concentration-dependent manner (IC
50,human
: 11 nmol/L; IC
50,monkey
: 49 nmol/L). ASP9521 showed >100-fold selectivity for AKR1C3 over the isoform AKR1C2. In LNCaP-AKR1C3 cells, ASP9521 suppressed AD-dependent PSA production and cell proliferation. In CWR22R xenografts, single oral administration of ASP9521 (3 mg/kg) inhibited AD-induced intratumoural T production and this inhibitory effect was maintained for 24 h. After oral administration, ASP9521 was rapidly eliminated from plasma, while its intratumoural concentration remained high. The bioavailability of ASP9521 after oral administration (1 mg/kg) was 35 %, 78 % and 58 % in rats, dogs and monkeys, respectively.
Conclusions
ASP9521 is a potent, selective, orally bioavailable AKR1C3 inhibitor. |
doi_str_mv | 10.1007/s10637-014-0130-5 |
format | article |
fullrecord | <record><control><sourceid>pubmed_cross</sourceid><recordid>TN_cdi_crossref_primary_10_1007_s10637_014_0130_5</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>24981575</sourcerecordid><originalsourceid>FETCH-LOGICAL-c414t-d71e167105a0012c2ae09bc4863c5627cd113faf9c4434f8d934bfecc290bf763</originalsourceid><addsrcrecordid>eNp9kMFu1DAQhi0EokvhAbggH0FqYCa24zU9rZZCKyqBKJwjx5l0XaXxyk4j8jo8Ag_CM9VhgSOH0Whm_v-X5mPsOcJrBNBvEkIldAEocwko1AO2QqVFAZWsHrIVYKWLyhh9xJ6kdAMAwmj5mB2V0qyzUK3Yj4uBT36Mgduh5X4ZpsDdzkbrRoo-2dGHgYeOb64-G1XiW275ECbqT3iintzoJzrhIdq-n3njg52s723TUw7b-caPIS5u1L9-Fru5jeH7nHJw8C1v6ffimgabiI_znrjiLxfl-dU7dco3H7_gVrx6yh51tk_07E8_Zt_en33dnheXnz5cbDeXhZMox6LVSPlfBGUBsHSlJTCNk-tKOFWV2rWIorOdcVIK2a1bI2TTkXOlgabTlThmeMh1MaQUqav30d_aONcI9cK7PvCuM-964V2r7Hlx8Ozvmltq_zn-As6C8iBI-TRcU6xvwl0c8h__Sb0HMA-MPw</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype></control><display><type>article</type><title>In vitro and in vivo characterisation of ASP9521: a novel, selective, orally bioavailable inhibitor of 17β-hydroxysteroid dehydrogenase type 5 (17βHSD5; AKR1C3)</title><source>ABI/INFORM Global</source><source>Springer Nature</source><creator>Kikuchi, Aya ; Furutani, Takashi ; Azami, Hidenori ; Watanabe, Kazushi ; Niimi, Tatsuya ; Kamiyama, Yoshiteru ; Kuromitsu, Sadao ; Baskin-Bey, Edwina ; Heeringa, Marten ; Ouatas, Taoufik ; Enjo, Kentaro</creator><creatorcontrib>Kikuchi, Aya ; Furutani, Takashi ; Azami, Hidenori ; Watanabe, Kazushi ; Niimi, Tatsuya ; Kamiyama, Yoshiteru ; Kuromitsu, Sadao ; Baskin-Bey, Edwina ; Heeringa, Marten ; Ouatas, Taoufik ; Enjo, Kentaro</creatorcontrib><description>Summary
Background
Aldo-keto reductase 1C3 [AKR1C3;17β-hydroxysteroid dehydrogenase type 5 (17βHSD5)], plays a crucial role in persistent production of androgens despite castration, by catalysing conversion of the adrenal androgens dehydroepiandrosterone and androstenedione (AD) into androstenediol and testosterone (T). Hence, AKR1C3 is a promising therapeutic target in castration-resistant prostate cancer, as combination of an AKR1C3 inhibitor and a gonadotropin-releasing hormone analogue may lead to complete androgen blockade. This study describes the preclinical characterisation of the novel AKR1C3 inhibitor ASP9521.
Methods
The inhibitory effect of ASP9521 on AKR1C3-mediated conversion from AD into T was evaluated both in vitro and in vivo, using CWR22R xenografted mice. The effect of ASP9521 on PSA production and cell proliferation was tested using LNCaP cells stably expressing human AKR1C3 (LNCaP-AKR1C3). Pharmacokinetics of ASP9521 were studied in rats, dogs and cynomolgus monkeys.
Results
ASP9521 inhibited conversion of AD into T by recombinant human or cynomolgus monkey AKR1C3 in a concentration-dependent manner (IC
50,human
: 11 nmol/L; IC
50,monkey
: 49 nmol/L). ASP9521 showed >100-fold selectivity for AKR1C3 over the isoform AKR1C2. In LNCaP-AKR1C3 cells, ASP9521 suppressed AD-dependent PSA production and cell proliferation. In CWR22R xenografts, single oral administration of ASP9521 (3 mg/kg) inhibited AD-induced intratumoural T production and this inhibitory effect was maintained for 24 h. After oral administration, ASP9521 was rapidly eliminated from plasma, while its intratumoural concentration remained high. The bioavailability of ASP9521 after oral administration (1 mg/kg) was 35 %, 78 % and 58 % in rats, dogs and monkeys, respectively.
Conclusions
ASP9521 is a potent, selective, orally bioavailable AKR1C3 inhibitor.</description><identifier>ISSN: 0167-6997</identifier><identifier>EISSN: 1573-0646</identifier><identifier>DOI: 10.1007/s10637-014-0130-5</identifier><identifier>PMID: 24981575</identifier><language>eng</language><publisher>New York: Springer US</publisher><subject>Administration, Oral ; Androstenedione - metabolism ; Animals ; Biological Availability ; Cell Line, Tumor ; Dogs ; Enzyme Inhibitors - blood ; Enzyme Inhibitors - pharmacokinetics ; Enzyme Inhibitors - pharmacology ; Estradiol Dehydrogenases - antagonists & inhibitors ; Humans ; Indoles - blood ; Indoles - pharmacokinetics ; Indoles - pharmacology ; Macaca fascicularis ; Male ; Medicine ; Medicine & Public Health ; Mice, Inbred BALB C ; Oncology ; Pharmacology/Toxicology ; Piperidines - blood ; Piperidines - pharmacokinetics ; Piperidines - pharmacology ; Preclinical Studies ; Prostatic Neoplasms - metabolism ; Rats ; Rats, Sprague-Dawley ; Testosterone - metabolism</subject><ispartof>Investigational new drugs, 2014-10, Vol.32 (5), p.860-870</ispartof><rights>Springer Science+Business Media New York 2014</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c414t-d71e167105a0012c2ae09bc4863c5627cd113faf9c4434f8d934bfecc290bf763</citedby><cites>FETCH-LOGICAL-c414t-d71e167105a0012c2ae09bc4863c5627cd113faf9c4434f8d934bfecc290bf763</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24981575$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Kikuchi, Aya</creatorcontrib><creatorcontrib>Furutani, Takashi</creatorcontrib><creatorcontrib>Azami, Hidenori</creatorcontrib><creatorcontrib>Watanabe, Kazushi</creatorcontrib><creatorcontrib>Niimi, Tatsuya</creatorcontrib><creatorcontrib>Kamiyama, Yoshiteru</creatorcontrib><creatorcontrib>Kuromitsu, Sadao</creatorcontrib><creatorcontrib>Baskin-Bey, Edwina</creatorcontrib><creatorcontrib>Heeringa, Marten</creatorcontrib><creatorcontrib>Ouatas, Taoufik</creatorcontrib><creatorcontrib>Enjo, Kentaro</creatorcontrib><title>In vitro and in vivo characterisation of ASP9521: a novel, selective, orally bioavailable inhibitor of 17β-hydroxysteroid dehydrogenase type 5 (17βHSD5; AKR1C3)</title><title>Investigational new drugs</title><addtitle>Invest New Drugs</addtitle><addtitle>Invest New Drugs</addtitle><description>Summary
Background
Aldo-keto reductase 1C3 [AKR1C3;17β-hydroxysteroid dehydrogenase type 5 (17βHSD5)], plays a crucial role in persistent production of androgens despite castration, by catalysing conversion of the adrenal androgens dehydroepiandrosterone and androstenedione (AD) into androstenediol and testosterone (T). Hence, AKR1C3 is a promising therapeutic target in castration-resistant prostate cancer, as combination of an AKR1C3 inhibitor and a gonadotropin-releasing hormone analogue may lead to complete androgen blockade. This study describes the preclinical characterisation of the novel AKR1C3 inhibitor ASP9521.
Methods
The inhibitory effect of ASP9521 on AKR1C3-mediated conversion from AD into T was evaluated both in vitro and in vivo, using CWR22R xenografted mice. The effect of ASP9521 on PSA production and cell proliferation was tested using LNCaP cells stably expressing human AKR1C3 (LNCaP-AKR1C3). Pharmacokinetics of ASP9521 were studied in rats, dogs and cynomolgus monkeys.
Results
ASP9521 inhibited conversion of AD into T by recombinant human or cynomolgus monkey AKR1C3 in a concentration-dependent manner (IC
50,human
: 11 nmol/L; IC
50,monkey
: 49 nmol/L). ASP9521 showed >100-fold selectivity for AKR1C3 over the isoform AKR1C2. In LNCaP-AKR1C3 cells, ASP9521 suppressed AD-dependent PSA production and cell proliferation. In CWR22R xenografts, single oral administration of ASP9521 (3 mg/kg) inhibited AD-induced intratumoural T production and this inhibitory effect was maintained for 24 h. After oral administration, ASP9521 was rapidly eliminated from plasma, while its intratumoural concentration remained high. The bioavailability of ASP9521 after oral administration (1 mg/kg) was 35 %, 78 % and 58 % in rats, dogs and monkeys, respectively.
Conclusions
ASP9521 is a potent, selective, orally bioavailable AKR1C3 inhibitor.</description><subject>Administration, Oral</subject><subject>Androstenedione - metabolism</subject><subject>Animals</subject><subject>Biological Availability</subject><subject>Cell Line, Tumor</subject><subject>Dogs</subject><subject>Enzyme Inhibitors - blood</subject><subject>Enzyme Inhibitors - pharmacokinetics</subject><subject>Enzyme Inhibitors - pharmacology</subject><subject>Estradiol Dehydrogenases - antagonists & inhibitors</subject><subject>Humans</subject><subject>Indoles - blood</subject><subject>Indoles - pharmacokinetics</subject><subject>Indoles - pharmacology</subject><subject>Macaca fascicularis</subject><subject>Male</subject><subject>Medicine</subject><subject>Medicine & Public Health</subject><subject>Mice, Inbred BALB C</subject><subject>Oncology</subject><subject>Pharmacology/Toxicology</subject><subject>Piperidines - blood</subject><subject>Piperidines - pharmacokinetics</subject><subject>Piperidines - pharmacology</subject><subject>Preclinical Studies</subject><subject>Prostatic Neoplasms - metabolism</subject><subject>Rats</subject><subject>Rats, Sprague-Dawley</subject><subject>Testosterone - metabolism</subject><issn>0167-6997</issn><issn>1573-0646</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><recordid>eNp9kMFu1DAQhi0EokvhAbggH0FqYCa24zU9rZZCKyqBKJwjx5l0XaXxyk4j8jo8Ag_CM9VhgSOH0Whm_v-X5mPsOcJrBNBvEkIldAEocwko1AO2QqVFAZWsHrIVYKWLyhh9xJ6kdAMAwmj5mB2V0qyzUK3Yj4uBT36Mgduh5X4ZpsDdzkbrRoo-2dGHgYeOb64-G1XiW275ECbqT3iintzoJzrhIdq-n3njg52s723TUw7b-caPIS5u1L9-Fru5jeH7nHJw8C1v6ffimgabiI_znrjiLxfl-dU7dco3H7_gVrx6yh51tk_07E8_Zt_en33dnheXnz5cbDeXhZMox6LVSPlfBGUBsHSlJTCNk-tKOFWV2rWIorOdcVIK2a1bI2TTkXOlgabTlThmeMh1MaQUqav30d_aONcI9cK7PvCuM-964V2r7Hlx8Ozvmltq_zn-As6C8iBI-TRcU6xvwl0c8h__Sb0HMA-MPw</recordid><startdate>20141001</startdate><enddate>20141001</enddate><creator>Kikuchi, Aya</creator><creator>Furutani, Takashi</creator><creator>Azami, Hidenori</creator><creator>Watanabe, Kazushi</creator><creator>Niimi, Tatsuya</creator><creator>Kamiyama, Yoshiteru</creator><creator>Kuromitsu, Sadao</creator><creator>Baskin-Bey, Edwina</creator><creator>Heeringa, Marten</creator><creator>Ouatas, Taoufik</creator><creator>Enjo, Kentaro</creator><general>Springer US</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope></search><sort><creationdate>20141001</creationdate><title>In vitro and in vivo characterisation of ASP9521: a novel, selective, orally bioavailable inhibitor of 17β-hydroxysteroid dehydrogenase type 5 (17βHSD5; AKR1C3)</title><author>Kikuchi, Aya ; Furutani, Takashi ; Azami, Hidenori ; Watanabe, Kazushi ; Niimi, Tatsuya ; Kamiyama, Yoshiteru ; Kuromitsu, Sadao ; Baskin-Bey, Edwina ; Heeringa, Marten ; Ouatas, Taoufik ; Enjo, Kentaro</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c414t-d71e167105a0012c2ae09bc4863c5627cd113faf9c4434f8d934bfecc290bf763</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><topic>Administration, Oral</topic><topic>Androstenedione - metabolism</topic><topic>Animals</topic><topic>Biological Availability</topic><topic>Cell Line, Tumor</topic><topic>Dogs</topic><topic>Enzyme Inhibitors - blood</topic><topic>Enzyme Inhibitors - pharmacokinetics</topic><topic>Enzyme Inhibitors - pharmacology</topic><topic>Estradiol Dehydrogenases - antagonists & inhibitors</topic><topic>Humans</topic><topic>Indoles - blood</topic><topic>Indoles - pharmacokinetics</topic><topic>Indoles - pharmacology</topic><topic>Macaca fascicularis</topic><topic>Male</topic><topic>Medicine</topic><topic>Medicine & Public Health</topic><topic>Mice, Inbred BALB C</topic><topic>Oncology</topic><topic>Pharmacology/Toxicology</topic><topic>Piperidines - blood</topic><topic>Piperidines - pharmacokinetics</topic><topic>Piperidines - pharmacology</topic><topic>Preclinical Studies</topic><topic>Prostatic Neoplasms - metabolism</topic><topic>Rats</topic><topic>Rats, Sprague-Dawley</topic><topic>Testosterone - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Kikuchi, Aya</creatorcontrib><creatorcontrib>Furutani, Takashi</creatorcontrib><creatorcontrib>Azami, Hidenori</creatorcontrib><creatorcontrib>Watanabe, Kazushi</creatorcontrib><creatorcontrib>Niimi, Tatsuya</creatorcontrib><creatorcontrib>Kamiyama, Yoshiteru</creatorcontrib><creatorcontrib>Kuromitsu, Sadao</creatorcontrib><creatorcontrib>Baskin-Bey, Edwina</creatorcontrib><creatorcontrib>Heeringa, Marten</creatorcontrib><creatorcontrib>Ouatas, Taoufik</creatorcontrib><creatorcontrib>Enjo, Kentaro</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><jtitle>Investigational new drugs</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Kikuchi, Aya</au><au>Furutani, Takashi</au><au>Azami, Hidenori</au><au>Watanabe, Kazushi</au><au>Niimi, Tatsuya</au><au>Kamiyama, Yoshiteru</au><au>Kuromitsu, Sadao</au><au>Baskin-Bey, Edwina</au><au>Heeringa, Marten</au><au>Ouatas, Taoufik</au><au>Enjo, Kentaro</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>In vitro and in vivo characterisation of ASP9521: a novel, selective, orally bioavailable inhibitor of 17β-hydroxysteroid dehydrogenase type 5 (17βHSD5; AKR1C3)</atitle><jtitle>Investigational new drugs</jtitle><stitle>Invest New Drugs</stitle><addtitle>Invest New Drugs</addtitle><date>2014-10-01</date><risdate>2014</risdate><volume>32</volume><issue>5</issue><spage>860</spage><epage>870</epage><pages>860-870</pages><issn>0167-6997</issn><eissn>1573-0646</eissn><abstract>Summary
Background
Aldo-keto reductase 1C3 [AKR1C3;17β-hydroxysteroid dehydrogenase type 5 (17βHSD5)], plays a crucial role in persistent production of androgens despite castration, by catalysing conversion of the adrenal androgens dehydroepiandrosterone and androstenedione (AD) into androstenediol and testosterone (T). Hence, AKR1C3 is a promising therapeutic target in castration-resistant prostate cancer, as combination of an AKR1C3 inhibitor and a gonadotropin-releasing hormone analogue may lead to complete androgen blockade. This study describes the preclinical characterisation of the novel AKR1C3 inhibitor ASP9521.
Methods
The inhibitory effect of ASP9521 on AKR1C3-mediated conversion from AD into T was evaluated both in vitro and in vivo, using CWR22R xenografted mice. The effect of ASP9521 on PSA production and cell proliferation was tested using LNCaP cells stably expressing human AKR1C3 (LNCaP-AKR1C3). Pharmacokinetics of ASP9521 were studied in rats, dogs and cynomolgus monkeys.
Results
ASP9521 inhibited conversion of AD into T by recombinant human or cynomolgus monkey AKR1C3 in a concentration-dependent manner (IC
50,human
: 11 nmol/L; IC
50,monkey
: 49 nmol/L). ASP9521 showed >100-fold selectivity for AKR1C3 over the isoform AKR1C2. In LNCaP-AKR1C3 cells, ASP9521 suppressed AD-dependent PSA production and cell proliferation. In CWR22R xenografts, single oral administration of ASP9521 (3 mg/kg) inhibited AD-induced intratumoural T production and this inhibitory effect was maintained for 24 h. After oral administration, ASP9521 was rapidly eliminated from plasma, while its intratumoural concentration remained high. The bioavailability of ASP9521 after oral administration (1 mg/kg) was 35 %, 78 % and 58 % in rats, dogs and monkeys, respectively.
Conclusions
ASP9521 is a potent, selective, orally bioavailable AKR1C3 inhibitor.</abstract><cop>New York</cop><pub>Springer US</pub><pmid>24981575</pmid><doi>10.1007/s10637-014-0130-5</doi><tpages>11</tpages></addata></record> |
fulltext | fulltext |
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ispartof | Investigational new drugs, 2014-10, Vol.32 (5), p.860-870 |
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language | eng |
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source | ABI/INFORM Global; Springer Nature |
subjects | Administration, Oral Androstenedione - metabolism Animals Biological Availability Cell Line, Tumor Dogs Enzyme Inhibitors - blood Enzyme Inhibitors - pharmacokinetics Enzyme Inhibitors - pharmacology Estradiol Dehydrogenases - antagonists & inhibitors Humans Indoles - blood Indoles - pharmacokinetics Indoles - pharmacology Macaca fascicularis Male Medicine Medicine & Public Health Mice, Inbred BALB C Oncology Pharmacology/Toxicology Piperidines - blood Piperidines - pharmacokinetics Piperidines - pharmacology Preclinical Studies Prostatic Neoplasms - metabolism Rats Rats, Sprague-Dawley Testosterone - metabolism |
title | In vitro and in vivo characterisation of ASP9521: a novel, selective, orally bioavailable inhibitor of 17β-hydroxysteroid dehydrogenase type 5 (17βHSD5; AKR1C3) |
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