Novel Human Aminopeptidase N Inhibitors: Discovery and Optimization of Subsite Binding Interactions

Lee Jisook; Vinh Natalie B.; Drinkwater Nyssa; Yang Wei; Sivaraman Komagal Kannan; Schembri Luke S.; Gazdik Michelle; Grin Peter M.; Butler Georgina S.; Overall Christopher M.; Charman Susan A.; McGowan Sheena; Scammells Peter J.

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Novel Human Aminopeptidase N Inhibitors: Discovery and Optimization of Subsite Binding Interactions

机译：新型人氨基肽酶N抑制剂：底座结合相互作用的发现和优化

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Aminopeptidase N (APN/CD13) is a zinc-dependent M1 aminopeptidase that contributes to cancer progression by promoting angiogenesis, metastasis, and tumor invasion. We have previously identified hydroxamic acid-containing analogues that are potent inhibitors of the APN homologue from the malarial parasite Plasmodium falciparum M1 aminopeptidase (PfA-M1). Herein, we describe the rationale that underpins the repurposing of PfA-MI inhibitors as novel APN inhibitors. A series of novel hydroxamic acid analogues were developed using a structure-based design approach and evaluated their inhibition activities against APN. N-(2-(Hydroxyamino)-2-oxo-1-(3',4',5'-trifluoro-[1,1'-biphenyl]-4-yOethyl)-4(methylsulfonamido)benzamide (6ad) proved to be an extremely potent inhibitor of APN activity in vitro, selective against other zinc-dependent enzymes such as matrix metalloproteases, and possessed limited cytotoxicity against Ad293 cells and favorable physicochemical and metabolic stability properties. The combined results indicate that compound 6ad may be a useful lead for the development of anticancer agents.

机译：氨肽酶N（APN / CD13）是锌依赖性M1氨基肽酶，其通过促进血管生成，转移和肿瘤侵袭有助于癌症进展。我们先前鉴定了含异羟肟酸的类似物，其是来自疟原虫寄生虫疟原虫M1氨基肽酶（PFA-M1）的APN同源物的有效抑制剂。在此，我们描述了基础抑制PFA-MI抑制剂作为新型APN抑制剂的理由。使用基于结构的设计方法开发了一系列新的羟肟酸类似物，并评估了对APN的抑制作用。 N-（2-（羟基氨基）-2-氧代-1-（3'，4'，5'-三氟-[1,1'-Biphenyl] -4- yo乙基）-4（甲基磺酰氨基）苯甲酰胺（6AD）证明作为体外的APN活性的极其有效的抑制剂，对诸如基质金属蛋白酶的其他锌依赖性酶选择，并且具有针对AD293细胞的有限细胞毒性，并且有利的物理化学和代谢稳定性。组合结果表明化合物6AD可能是一种有用的领导抗癌剂的发展。

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《Journal of Medicinal Chemistry》 |2019年第15期|共25页
作者
Lee Jisook; Vinh Natalie B.; Drinkwater Nyssa; Yang Wei; Sivaraman Komagal Kannan; Schembri Luke S.; Gazdik Michelle; Grin Peter M.; Butler Georgina S.; Overall Christopher M.; Charman Susan A.; McGowan Sheena; Scammells Peter J.;
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Monash Univ Monash Inst Pharmaceut Sci Med Chem Parkville Campus Parkville Vic 3052 Australia;

Monash Univ Monash Inst Pharmaceut Sci Med Chem Parkville Campus Parkville Vic 3052 Australia;

Monash Univ Infect &

Immun Program Biomed Discovery Inst Clayton Campus Clayton Vic 3800 Australia;

Monash Univ Infect &

Immun Program Biomed Discovery Inst Clayton Campus Clayton Vic 3800 Australia;

Monash Univ Infect &

Immun Program Biomed Discovery Inst Clayton Campus Clayton Vic 3800 Australia;

Monash Univ Monash Inst Pharmaceut Sci Med Chem Parkville Campus Parkville Vic 3052 Australia;

Monash Univ Monash Inst Pharmaceut Sci Med Chem Parkville Campus Parkville Vic 3052 Australia;

Univ British Columbia Life Sci Inst Dept Biochem &

Mol Biol Vancouver BC V6T 1Z3 Canada;

Univ British Columbia Life Sci Inst Dept Biochem &

Mol Biol Vancouver BC V6T 1Z3 Canada;

Univ British Columbia Life Sci Inst Dept Biochem &

Mol Biol Vancouver BC V6T 1Z3 Canada;

Monash Univ Monash Inst Pharmaceut Sci Ctr Drug Candidate Optimisat Parkville Campus Parkville Vic 3052 Australia;

Monash Univ Infect &

Immun Program Biomed Discovery Inst Clayton Campus Clayton Vic 3800 Australia;

Monash Univ Monash Inst Pharmaceut Sci Med Chem Parkville Campus Parkville Vic 3052 Australia;

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1. Novel Human Aminopeptidase N Inhibitors: Discovery and Optimization of Subsite Binding Interactions [J] . Lee Jisook, Vinh Natalie B., Drinkwater Nyssa, Journal of Medicinal Chemistry . 2019,第15期

机译：新型人氨基肽酶N抑制剂：底座结合相互作用的发现和优化
2. Discovery and optimization of anthranilic acid sulfonamides as inhibitors of methionine aminopeptidase-2: A structural basis for the reduction of albumin binding [J] . Sheppard GS, Wang JY, Kawai M, Journal of Medicinal Chemistry . 2006,第13期

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3. Optimization of subsite binding to the beta 5 subunit of the human 20S proteasome using vinyl sulfones and 2-keto-1,3,4-oxadiazoles: Syntheses and cellular properties of potent, selective proteasome inhibitors [J] . Rydzewski RM, Burrill L, Mendonca R, Journal of Medicinal Chemistry . 2006,第10期

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4. Probing the Interaction Between HIV-1 Surface Envelope Glycoprotein gpl20 and Its Cell Co-Receptor CCR5 Using Photoactivatable CCR5-Derived Peptides to Guide Discovery and Optimization of Novel HIV-1 Entry Inhibitors [C] . Kostyantyn D. Bobyk, Sivakoteswara R. Madapu, Katheryn Lohith, PEGS . 2015

机译：利用光活化CCR5衍生肽探测HIV-1表面包膜糖蛋白GPL20及其细胞共同受体CCR5的相互作用，以指导新型HIV-1进入抑制剂的发现和优化
5. Characterization of a Human Immunodeficiency Virus (HIV) Type I Integrase Inhibitor-Binding Pocket and Discovery of Novel Inhibitors Potent against Drug-Resistant Variants of HIV [D] . Crosby, David Charles 2010

机译：人类免疫缺陷病毒（HIV）I型整合酶抑制剂结合口袋的表征和新型抗HIV药物耐药变体的抑制剂的发现
6. Mechanism-Based Inhibitors of Serine Proteases with High Selectivity Through Optimization of S’ Subsite Binding [O] . Yi Li, Dengfeng Dou, Guijia He, -1

机译：具有高选择性的丝氨酸蛋白酶的机制为基础的抑制剂通过s子网站的优化结合
7. Structure-directed discovery of potent non-peptidic inhibitors of human urokinase that access a novel binding subsite [O] . Nienaber Vicki L, Davidson Donald, Edalji Rohinton, 2000

机译：结构导向的人类尿激酶有效非肽类抑制剂的发现，该抑制剂可进入新的结合亚位点

Novel Human Aminopeptidase N Inhibitors: Discovery and Optimization of Subsite Binding Interactions

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