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

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.
Tuomo Kalliokoski 1,  Henna Kettunen 2,  Esa Kumpulainen 3,  Emilia Kettunen 2,  Gabriel Thieulin-Pardo 4,  Lars Neumann 4,  Maren Thomsen 4,  Ralf Paul 2,  Alina Malyutina 3,  Maria Georgiadou 2
Affiliations

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.

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