1. Academic Validation
  2. Targeting mPGES-1 by a Combinatorial Approach: Identification of the Aminobenzothiazole Scaffold to Suppress PGE2 Levels

Targeting mPGES-1 by a Combinatorial Approach: Identification of the Aminobenzothiazole Scaffold to Suppress PGE2 Levels

  • ACS Med Chem Lett. 2020 Mar 5;11(5):783-789. 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
Affiliations

Affiliations

  • 1 Department of Pharmacy, University of Salerno, via Giovanni Paolo II, 132, 84084, Fisciano, Italy.
  • 2 Department of Biosciences and Territory, University of Molise, Contrada Fonte Lappone, Pesche, Isernia, I-86090, Italy.
  • 3 Institute of Biomolecular Chemistry (ICB), Consiglio Nazionale delle Ricerche (CNR), Via Campi Flegrei 34, I-80078, Pozzuoli, Napoli, Italy.
  • 4 Department of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Friedrich Schiller University Jena, Jena, Germany.
  • 5 Michael Popp Research Institute, University of Innsbruck, Innsbruck, Austria.
Abstract

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).

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