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

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

Affiliations

  • 1 Mirati Therapeutics, San Diego, CA 92121, United States. Electronic address: smithc@mirati.com.
  • 2 Mirati Therapeutics, San Diego, CA 92121, United States.
  • 3 Mirati Therapeutics, San Diego, CA 92121, United States. Electronic address: kulyks@mirati.com.
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.

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