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.
Christopher R Smith  1 ,  Ruth Aranda  2 ,  James G Christensen  2 ,  Lars D Engstrom  2 ,  Robin J Gunn  2 ,  Anthony Ivetac  2 ,  John M Ketcham  2 ,  Jon Kuehler  2 ,  J David Lawson  2 ,  Matthew A Marx  2 ,  Peter Olson  2 ,  Nicole C Thomas  2 ,  Xiaolun Wang  2 ,  Laura M Waters  2 ,  Svitlana Kulyk  3
Affiliations
  • 1. Mirati Therapeutics, San Diego, CA 92121, United States. Electronic address: [email protected].
  • 2. Mirati Therapeutics, San Diego, CA 92121, United States.
  • 3. Mirati Therapeutics, San Diego, CA 92121, United States. Electronic address: [email protected].
PMID: 35926325 DOI: 10.1016/j.bmc.2022.116947
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.