Development of potent and selective indomethacin analogues for the inhibition of AKR1C3 (Type 5 17β-hydroxysteroid dehydrogenase/prostaglandin F synthase) in castrate-resistant prostate cancer.
Development of potent and selective indomethacin analogues for the inhibition of AKR1C3 (Type 5 17β-hydroxysteroid dehydrogenase/prostaglandin F synthase) in castrate-resistant prostate cancer.
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DOI：
10.1021/jm3017656
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发表时间：
2013-03-28
影响因子：
7.3
通讯作者：
Penning, Trevor M.
中科院分区：
文献类型：
--
作者：
Liedtke, Andy J.;Adeniji, Adegoke O.;Chen, Mo;Byrns, Michael C.;Jin, Yi;Christianson, David W.;Marnett, Lawrence J.;Penning, Trevor M.
去势抵抗性前列腺癌（CRPC）是一种致命的转移性前列腺癌。CRPC的特征在于由于雄激素受体信号传导和/或适应性瘤内雄激素生物合成的变化而导致的雄激素轴的再活化。AKR 1C 3在CRPC中上调，在那里它催化强效雄激素的形成。这使得AKR 1C 3成为CRPC治疗的靶点。AKR 1C 3抑制剂不应抑制AKR 1C 1/AKR 1C 2，其抑制5α-二氢睾酮。吲哚美辛，用于抑制环氧合酶，也抑制AKR 1C 3和AKR 1C 1/AKR 1C 2显示选择性。平行合成策略用于产生吲哚美辛类似物的文库，其表现出降低的环氧合酶抑制活性，但保留AKR 1C 3抑制效力和选择性。先导化合物以纳摩尔效力抑制AKR 1C 3，显示超过AKR 1C 1/AKR 1C 2>100倍的选择性，并阻断LNCaP-AKR 1C 3细胞中的睾酮形成。测定了AKR 1C 3·NADP+·2′-去甲基吲哚美辛的晶体结构，揭示了其独特的抑制剂结合模式。所报道的化合物是用于开发CRPC治疗剂的有前景的药剂。
Castrate-resistant prostate cancer (CRPC) is a fatal, metastatic form of prostate cancer. CRPC is characterized by reactivation of the androgen axis due to changes in androgen receptor signaling and/or adaptive intratumoral androgen biosynthesis. AKR1C3 is upregulated in CRPC where it catalyzes the formation of potent androgens. This makes AKR1C3 a target for the treatment of CRPC. AKR1C3 inhibitors should not inhibit AKR1C1/AKR1C2, which inactivate 5α-dihydrotestosterone. Indomethacin, used to inhibit cyclooxygenase, also inhibits AKR1C3 and displays selectivity over AKR1C1/AKR1C2. Parallel synthetic strategies were used to generate libraries of indomethacin analogues, which exhibit reduced cyclooxygenase inhibitory activity but retain AKR1C3 inhibitory potency and selectivity. The lead compounds inhibited AKR1C3 with nanomolar potency, displayed >100-fold selectivity over AKR1C1/AKR1C2, and blocked testosterone formation in LNCaP-AKR1C3 cells. The AKR1C3·NADP+·2′-des-methyl-indomethacin crystal structure was determined, and it revealed a unique inhibitor binding mode. The compounds reported are promising agents for the development of therapeutics for CRPC.
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DOI：
10.1016/j.jsbmb.2010.11.004
发表时间：
2011-05
影响因子：
4.1
作者：
Byrns, Michael C.;Jin, Yi;Penning, Trevor M.
通讯作者：
Penning, Trevor M.
DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
影响因子：
3.6
作者：
CONN, RSE;DOUGLAS, AW;SHINKAI, I
通讯作者：
SHINKAI, I
影响因子：
7.3
作者：
Adeniji, Adegoke O.;Twenter, Barry M.;Byrns, Michael C.;Jin, Yi;Chen, Mo;Winkler, Jeffrey D.;Penning, Trevor M.
通讯作者：
Penning, Trevor M.
DOI：
10.1107/s0907444909052925
发表时间：
2010-02
期刊：
Acta crystallographica. Section D, Biological crystallography
影响因子：
--
作者：
Adams PD;Afonine PV;Bunkóczi G;Chen VB;Davis IW;Echols N;Headd JJ;Hung LW;Kapral GJ;Grosse-Kunstleve RW;McCoy AJ;Moriarty NW;Oeffner R;Read RJ;Richardson DC;Richardson JS;Terwilliger TC;Zwart PH
通讯作者：
Zwart PH