ASP9521 is a potent, selective and orally available AKR1C3 inhibitor with an IC50 of 11 nM for human AKR1C3. ASP9521 inhibited conversion of androstenedione (AD) into testosterone (T) by recombinant human or cynomolgus monkey AKR1C3 in a concentration-dependent manner (IC50,human: 11 nmol/L; IC50,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 vivo, single oral administration of ASP-9521 (3 mg/kg) inhibits AD-induced intratumoural T production in CWR22R xenografts, and this inhibitory effect is maintained for 24 h. After oral administration, ASP-9521 is rapidly eliminated from plasma, while its intratumoural concentration remained high. The bioavailability of ASP9521 after oral administration (1 mg/kg) is 35 %, 78 % and 58 % in rats, dogs and monkeys, respectively.
|Cell lines||LNCaP-AKR1C3 cells stably expressing human AKR1C3|
|Preparation method||LNCaP-AKR1C3 cells stably expressing human AKR1C3 are seeded in 96-well plates at 10000 cells/100 μL/well in RPMI-1640 medium supplemented with heat-inactivated charcoal-dextran-stripped FBS (1 % for the PSA expression assay and T measurement and 5 % for the cell proliferation assay). After 24 h incubation, AD is added to each well with or without ASP-9521 (0.3-100 nM). The cell culture media are collected 24 h after administration of AD to measure T concentration and 6 days after administration of AD to measure cell proliferation using Cell-Titer Glo assay.|
|Incubation time||24 h|
|Animal models||Mice carrying HEK293 or HEK293-AKR1C3 tumours|
|Formulation||0.5 % methyl cellulose|
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.
|Solubility||DMSO: ≥ 100 mg/mL|
In vitro and in vivo characterisation of ASP9521: a novel, selective, orally bioavailable inhibitor of 17β-hydroxysteroid dehydrogenase type 5 (17βHSD5; AKR1C3).
Kikuchi A, et al. Invest New Drugs. 2014 Oct;32(5):860-70. PMID: 24981575.
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