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
  • 1. Orion Pharma, Orionintie 1A, 02101 Espoo, Finland. Electronic address: [email protected].
  • 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.
Products