Targeting mPGES-1 by a Combinatorial Approach: Identification of the Aminobenzothiazole Scaffold to Suppress PGE2 Levels.,ACS Medicinal Chemistry Letters

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Targeting mPGES-1 by a Combinatorial Approach: Identification of the Aminobenzothiazole Scaffold to Suppress PGE2 Levels.
ACS Medicinal Chemistry Letters ( IF 3.5 ) Pub Date : 2020-03-05 , DOI: 10.1021/acsmedchemlett.9b00618
Maria G Chini _{1,

2} , Assunta Giordano _{1,

3} , Marianna Potenza ₁ , Stefania Terracciano ₁ , Katrin Fischer ₄ , Maria C Vaccaro ₁ , Ester Colarusso ₁ , Ines Bruno ₁ , Raffaele Riccio ₁ , Andreas Koeberle _{4,

5} , Oliver Werz ₄ , Giuseppe Bifulco ₁

Affiliation

Microsomal prostaglandin E2 synthase-1 (mPGES-1), the terminal enzyme responsible for the production of inducible prostaglandin E2, has become an attractive target for the treatment of inflammation and cancer pathologies. Starting from an aminobenzothiazole scaffold, used as an unprecedented chemical core for mPGES-1 inhibition, a Combinatorial Virtual Screening campaign was conducted, using the X-ray crystal structure of human mPGES-1. Two combinatorial libraries (6 × 104) were obtained by decorating the aminobenzothiazole scaffold with all acyl chlorides and boronates available at the Merck database. The scientific multidisciplinary approach included virtual screening workflow, synthesis, and biological evaluation and led to the identification of three novel aminobenzothiazoles 1, 3, and 13 acting as mPGES-1 inhibitors. The three disclosed hits are able to inhibit mPGES-1 in a cell-free system (IC50 = 1.4 ± 0.2, 0.7 ± 0.1, and 1.7 ± 0.2 μM, respectively), and all are endowed with antitumoral properties against A549 human cancer cell lines at micromolar concentrations (28.5 ± 1.1, 18.1 ± 0.8, and 19.2 ± 1.3 μM, respectively).

中文翻译：

通过组合方法靶向mPGES-1：识别氨基苯并噻唑支架以抑制PGE2水平。

微粒体前列腺素E2合酶1（mPGES-1）是负责诱导型前列腺素E2产生的末端酶，已成为治疗炎症和癌症的诱人靶标。从用作mPGES-1抑制作用的空前化学核心的氨基苯并噻唑支架开始，利用人mPGES-1的X射线晶体结构进行了组合虚拟筛选运动。通过用Merck数据库中可用的所有酰氯和硼酸酯修饰氨基苯并噻唑支架，获得了两个组合库（6×104）。科学的多学科方法包括虚拟筛选工作流程，合成和生物学评估，并导致鉴定出三种新型的mPGES-1抑制剂氨基苯并噻唑1、3和13。

更新日期：2020-03-05

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