Discovery of non-boronic acid Arginase 1 inhibitors through virtual screening and biophysical methods.

Autor: Gathiaka S; Computational & Structural Chemistry, Merck & Co., Inc., Boston, MA 02115, USA. Electronic address: symon.gathiaka@gmail.com., Palte RL; Computational & Structural Chemistry, Merck & Co., Inc., Boston, MA 02115, USA., So SS; Computational & Structural Chemistry, Merck & Co., Inc., Kenilworth, NJ 07033, USA., Chai X; Quantitative Biosciences, Merck & Co., Inc., Boston, NJ 02115, USA., Richard Miller J; Quantitative Biosciences, Merck & Co., Inc., Boston, MA 02115, USA., Kuvelkar R; Screening, Target and Compound Profiling, Merck & Co., Inc., Kenilworth, NJ 07033, USA., Wen X; Computational & Structural Chemistry, Merck & Co., Inc., Boston, MA 02115, USA., Cifelli S; Screening, Target and Compound Profiling, Merck & Co., Inc., Kenilworth, NJ 07033, USA., Kreamer A; Screening, Target and Compound Profiling, Merck & Co., Inc., Kenilworth, NJ 07033, USA., Liaw A; Biometrics Research, Merck & Co., Inc., Rahway, 90 E Scott Ave, Rahway, NJ 07065, USA., McLaren DG; Computational & Structural Chemistry, Merck & Co., Inc., Boston, MA 02115, USA., Fischer C; Discovery Chemistry, Merck & Co., Inc., Boston, MA 02115, USA.
Jazyk: angličtina
Zdroj: Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2023 Mar 15; Vol. 84, pp. 129193. Date of Electronic Publication: 2023 Feb 21.
DOI: 10.1016/j.bmcl.2023.129193
Abstrakt: Inhibiting Arginase 1 (ARG1), a metalloenzyme that hydrolyzes l-arginine in the urea cycle, has been demonstrated as a promising therapeutic avenue in immuno-oncology through the restoration of suppressed immune response in several types of cancers. Most of the currently reported small molecule inhibitors are boronic acid based. Herein, we report the discovery of non-boronic acid ARG1 inhibitors through virtual screening. Biophysical and biochemical methods were used to experimentally profile the hits while X-ray crystallography confirmed a class of trisubstituted pyrrolidine derivatives as optimizable alternatives for the development of novel classes of immuno-oncology agents targeting this enzyme.
Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2023 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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