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Targeting mPGES‑1 by a Combinatorial Approach: Identification of the Aminobenzothiazole Scaffold to Suppress PGE2 Levels
Version 2 2020-03-31, 13:04
Version 1 2020-03-10, 11:42
journal contribution
posted on 2020-03-31, 13:04 authored by Maria
G. Chini, Assunta Giordano, Marianna Potenza, Stefania Terracciano, Katrin Fischer, Maria C. Vaccaro, Ester Colarusso, Ines Bruno, Raffaele Riccio, Andreas Koeberle, Oliver Werz, Giuseppe BifulcoMicrosomal 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).