Chini Maria G, Giordano Assunta, Potenza Marianna, Terracciano Stefania, Fischer Katrin, Vaccaro Maria C, Colarusso Ester, Bruno Ines, Riccio Raffaele, Koeberle Andreas, Werz Oliver, Bifulco Giuseppe
Department of Pharmacy, University of Salerno, via Giovanni Paolo II, 132, 84084, Fisciano, Italy.
Department of Biosciences and Territory, University of Molise, Contrada Fonte Lappone, Pesche, Isernia, I-86090, Italy.
ACS Med Chem Lett. 2020 Mar 5;11(5):783-789. doi: 10.1021/acsmedchemlett.9b00618. eCollection 2020 May 14.
Microsomal prostaglandin E synthase-1 (mPGES-1), the terminal enzyme responsible for the production of inducible prostaglandin E, 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 × 10) 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 , , and acting as mPGES-1 inhibitors. The three disclosed hits are able to inhibit mPGES-1 in a cell-free system (IC = 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).
微粒体前列腺素E合酶-1（mPGES-1）是负责诱导型前列腺素E生成的终端酶，已成为治疗炎症和癌症病理的一个有吸引力的靶点。从用作mPGES-1抑制的前所未有的化学核心的氨基苯并噻唑支架出发，利用人mPGES-1的X射线晶体结构开展了组合虚拟筛选活动。通过用默克数据库中所有可用的酰氯和硼酸酯修饰氨基苯并噻唑支架，获得了两个组合库（6×10）。这种科学的多学科方法包括虚拟筛选流程、合成和生物学评估，并导致鉴定出三种新型氨基苯并噻唑，即化合物、和，它们可作为mPGES-1抑制剂。公开的这三个活性化合物能够在无细胞系统中抑制mPGES-1（IC分别为1.4±0.2、0.7±0.1和1.7±0.2μM），并且在微摩尔浓度下（分别为28.5±1.1、18.1±0.8和19.2±1.3μM）均具有针对A549人癌细胞系的抗肿瘤特性。
