Discovery of novel methionine adenosyltransferase 2A (MAT2A) allosteric inhibitors by structure-based virtual screening

Tuomo Kalliokoski; Henna Kettunen; Esa Kumpulainen; Emilia Kettunen; Gabriel Thieulin-Pardo; Lars Neumann; Maren Thomsen; Ralf Paul; Alina Malyutina; Maria Georgiadou

doi:10.1016/j.bmcl.2023.129450

Discovery of novel methionine adenosyltransferase 2A (MAT2A) allosteric inhibitors by structure-based virtual screening

Bioorg Med Chem Lett. 2023 Oct 1:94:129450. doi: 10.1016/j.bmcl.2023.129450. Epub 2023 Aug 15.

Authors

Affiliations

¹ Orion Pharma, Orionintie 1A, 02101 Espoo, Finland. Electronic address: tuomo.kalliokoski@orionpharma.com.
² Orion Pharma, Tengströminkatu 8, 20380 Turku, Finland.
³ Orion Pharma, Orionintie 1A, 02101 Espoo, Finland.
⁴ Proteros Biostructures GmbH, Bunsenstraβe 7a, D - 82152 Martinsried, Germany.

PMID: 37591318
DOI: 10.1016/j.bmcl.2023.129450

Abstract

Methionine adenosyltransferase 2A (MAT2A) has been indicated as a drug target for oncology indications. Clinical trials with MAT2A inhibitors are currently on-going. Here, a structure-based virtual screening campaign was performed on the commercially available chemical space which yielded two novel MAT2A-inhibitor chemical series. The binding modes of the compounds were confirmed with X-ray crystallography. Both series have acceptable physicochemical properties and show nanomolar activity in the biochemical MAT2A inhibition assay and single-digit micromolar activity in the proliferation assay (MTAP -/- cell line). The identified compounds and the relating structural data could be helpful in related drug discovery projects.

Keywords: Allosteric inhibitor; Methionine adenosyltransferase 2A (MAT2A); Methylthioadenosine phosphorylase (MTAP); Structure-based virtual screening.

MeSH terms

Biological Assay*
Cell Line
Crystallography, X-Ray
Methionine Adenosyltransferase* / antagonists & inhibitors
Molecular Targeted Therapy

Substances

MAT2A protein, human
Methionine Adenosyltransferase