Inhibitors of type 5 17β-hydroxysteroid dehydrogenase (AKR1C3): overview and structural insights.
Inhibitors of type 5 17β-hydroxysteroid dehydrogenase (AKR1C3): overview and structural insights.
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DOI：
10.1016/j.jsbmb.2010.11.004
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发表时间：
2011-05
影响因子：
4.1
通讯作者：
Penning, Trevor M.
中科院分区：
文献类型：
--
作者：
Byrns, Michael C.;Jin, Yi;Penning, Trevor M.
关键词：
人们对开发醛酮还原酶（AKR）1C 3（5型17β-羟类固醇脱氢酶和前列腺素F合酶）抑制剂作为激素依赖性和激素非依赖性癌症的潜在治疗药物非常感兴趣。AKR 1C 3催化靶组织中4-雄烯-3，17-二酮还原为睾酮，雌酮还原为17β-雌二醇，这将分别促进激素依赖性前列腺癌和乳腺癌的增殖。AKR 1C 3还催化前列腺素（PG）H2还原为PGF 2 α和PGD 2还原为9α，11 β-PGF 2，这将限制抗增殖的前列腺素（包括15-脱氧-Δ 12，14-PGJ 2）的形成，并有助于增殖信号传导。AKR 1C 3在多种癌症中过表达，包括乳腺癌和前列腺癌。AKR 1C 3的抑制剂不应抑制密切相关的亚型AKR 1C 1和AKR 1C 2，因为它们参与靶组织中的其他关键类固醇激素生物转化。已经探索了几种结构先导物作为AKR 1C 3的抑制剂，包括非甾体抗炎药、甾体激素类似物、类黄酮、环戊烷和苯并二氮杂卓。检查具有结合的多个配体的AKR 1C 3的可用晶体结构沿着其他AKR 1C同种型的晶体结构，为AKR 1C 3的同种型特异性抑制剂的合理设计提供了结构基础。我们发现，有参与配体结合的亚口袋，在AKR 1C 3相对于密切相关的AKR 1C 1或AKR 1C 2亚型有很大的不同。这些口袋可用于进一步改善目前可用的AKR 1C 3抑制剂的结合亲和力和选择性。
There is considerable interest in the development of an inhibitor of aldo-keto reductase (AKR) 1C3 (type 5 17β-hydroxysteroid dehydrogenase and prostaglandin F synthase) as a potential therapeutic for both hormone-dependent and hormone-independent cancers. AKR1C3 catalyzes the reduction of 4-androstene-3,17-dione to testosterone and estrone to 17β-estradiol in target tissues, which will promote the proliferation of hormone dependent prostate and breast cancers, respectively. AKR1C3 also catalyzes the reduction of prostaglandin (PG) H2 to PGF2α and PGD2 to 9α,11β-PGF2, which will limit the formation of anti-proliferative prostaglandins, including 15-deoxy-Δ12,14-PGJ2, and contribute to proliferative signaling. AKR1C3 is overexpressed in a wide variety of cancers, including breast and prostate cancer. An inhibitor of AKR1C3 should not inhibit the closely related isoforms AKR1C1 and AKR1C2, as they are involved in other key steroid hormone biotransformations in target tissues. Several structural leads have been explored as inhibitors of AKR1C3, including non-steroidal anti-inflammatory drugs, steroid hormone analogues, flavonoids, cyclopentanes, and benzodiazepines. Inspection of the available crystal structures of AKR1C3 with multiple ligands bound, along with the crystal structures of the other AKR1C isoforms, provides a structural basis for the rational design of isoform specific inhibitors of AKR1C3. We find that there are subpockets involved in ligand binding that are considerably different in AKR1C3 relative to the closely related AKR1C1 or AKR1C2 isoforms. These pockets can be used to further improve the binding affinity and selectivity of the currently available AKR1C3 inhibitors.
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影响因子：
--
作者：
Bauman, DR;Steckelbroeck, S;Penning, TM
通讯作者：
Penning, TM
影响因子：
11.2
作者：
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通讯作者：
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影响因子：
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通讯作者：
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影响因子：
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作者：
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通讯作者：
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影响因子：
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作者：
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通讯作者：
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