Design and evaluation of achiral, non-atropisomeric 4-(aminomethyl)phthalazin-1(2H)-one derivatives as novel PRMT5/MTA inhibitors

Bioorg Med Chem. 2022 Oct 1;71:116947. doi: 10.1016/j.bmc.2022.116947. Epub 2022 Jul 26.

Abstract

MRTX1719 is an inhibitor of the PRMT5/MTA complex and recently entered clinical trials for the treatment of MTAP-deleted cancers. MRTX1719 is a class 3 atropisomeric compound that requires a chiral synthesis or a chiral separation step in its preparation. Here, we report the SAR and medicinal chemistry design strategy, supported by structural insights from X-ray crystallography, to discover a class 1 atropisomeric compound from the same series that does not require a chiral synthesis or a chiral separation step in its preparation.

Keywords: Atropisomer; MRTX1719; MTA; MTAP; PRMT5; Structure-based drug design.

MeSH terms

  • Crystallography, X-Ray
  • Enzyme Inhibitors* / pharmacology
  • Humans
  • Neoplasms* / drug therapy
  • Phthalazines* / pharmacology
  • Protein-Arginine N-Methyltransferases

Substances

  • Enzyme Inhibitors
  • Phthalazines
  • PRMT5 protein, human
  • Protein-Arginine N-Methyltransferases
  • 4-(aminomethyl)phthalazin-1(2H)-one