DEVELOPMENT OF ANTITUMOR DRUGS TARGETING TUMOR MARKERALDO-KETO REDUCTASES

开发针对肿瘤标记酮还原酶的抗肿瘤药物

• 批准号: 22590102
• 负责人: HARA Akira
• 金额: $ 3万
• 依托单位: Gifu Pharmaceutical University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2010
• 资助国家: 日本
• 起止时间: 2010 至 2012
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-22590102/
• 关键词: 医薬品化学・医薬分子設計; ヒドロキシステロイド脱水素酵素; アルドーケト還元酵素; 制癌剤; 抗癌剤耐性; 阻害剤; 高次構造; アルドース還元酵素; 医薬品設計

Five aldo-keto reductases (AKR1C1, AKR1C3, AKR1C21, AKR1B1 andAKR1B10) are regarded as both diagnostic markers and therapeutic targets in the treatment of several types of cancer. We searched inhibitors of the enzymes, investigated selectivity determinants of the inhibitor-binding to the enzymes, and synthesized potent and selective inhibitors. (1) AKR1C1 inhibitor: Potent salicylic acid-based inhibitorswere synthesized based on the crystal structure of the enzyme. (2) AKR1C3 inhibitor: Among the inhibitors found, tolfenamic acid and baccharin were the most potent and selective inhibitors, respectively. A baccharin derivative with high inhibitory potency and selectivity was synthesized. (3) AKR1C21 inhibitor: Cholanic acid and its derivatives were found to be potent inhibitors. (4) AKR1B1 inhibitor: A selective and potent inhibitorwas synthesized based on the structure of an alkaloid rhetsinine. (4) AKR1B10 inhibitor:Some drugs (such as mefenamic acid) and natural products (mangostin, oleanolic acid,caffeic acid phenethyl ester) were found to be selective inhibitors. A caffeic acid phenethyl ester derivative with high inhibitory potency and selectivity was synthesized.

五种醛酮还原酶（AKR1C1、AKR1C3、AKR1C21、AKR1B1 和 AKR1B10）被视为多种癌症治疗的诊断标志物和治疗靶点。我们搜索了酶的抑制剂，研究了抑制剂与酶结合的选择性决定因素，并合成了有效的选择性抑制剂。 (1)AKR1C1抑制剂：根据酶的晶体结构合成了有效的水杨酸抑制剂。 (2)AKR1C3抑制剂：在已发现的抑制剂中，托芬那酸和巴糖精分别是最有效和选择性最强的抑制剂。合成了具有高抑制效力和选择性的酒精衍生物。 (3)AKR1C21抑制剂：胆酸及其衍生物被发现是有效的抑制剂。 (4)AKR1B1抑制剂：根据生物碱大黄碱的结构合成了一种选择性强效抑制剂。 (4)AKR1B10抑制剂：一些药物(如甲芬那酸)和天然产物(山竹素、齐墩果酸、咖啡酸苯乙酯)被发现是选择性抑制剂。合成了具有高抑制效力和选择性的咖啡酸苯乙酯衍生物。

项目成果

Studies on a Tyr residue critical for the binding of coenzyme and substrate in mouse 3(17)α-hydroxysteroid dehydrogenase (AKR1C21)

对小鼠 3(17)α-羟基类固醇脱氢酶 (AKR1C21) 中辅酶和底物结合至关重要的酪氨酸残基的研究

• 发表时间: 2010
• 期刊: Acta Crystallogr.D Biol.Crystallogr.
• 作者: U.Dhagat;S.Endo;H.Mamiya;A.Hara;O.El-Kabbani
• 通讯作者: O.El-Kabbani

Aldehyde reductase structures complexed with aldose reductase inhibitors: Implications for inhibitor selectivity

与醛糖还原酶抑制剂复合的醛还原酶结构：对抑制剂选择性的影响

• 发表时间: 2010
• 作者: Carbone V;Hara A;El-Kabbani O.RESEARCH SIGNPOST Publisher
• 通讯作者: El-Kabbani O.RESEARCH SIGNPOST Publisher

Advances in molecular mechanisms and pharmacology of diabetic complications

糖尿病并发症的分子机制和药理学研究进展

• 发表时间: 2010
• 作者: V.Carbone;A.Hara;O.El-Kabbani
• 通讯作者: O.El-Kabbani

肺癌細胞のシスプラチン耐性に対するアルドケト還元酵素1B10阻害剤の有用性

醛酮还原酶 1B10 抑制剂对抗肺癌细胞顺铂耐药的效用

• 作者: Motoi Ohba;Tohru Ohmori;Toshio Kurokiand Etsuko Toya;友國琢允
• 通讯作者: 友國琢允

Pathophysiological roles of aldo-keto reductases (AKR1C1 and AKR1C3) in development of cisplatin resistance in human colon Cancers

• DOI: 10.1016/j.cbi.2012.09.024
• 发表时间: 2013-02-25
• 期刊: CHEMICO-BIOLOGICAL INTERACTIONS
• 影响因子: 5.1
• 作者: Matsunaga, Toshiyuki;Hojo, Aki;Hara, Akira
• 通讯作者: Hara, Akira