Discovery and Optimization of N-Arylated Tetracyclic Dicarboximides That Target Primary Glioma Stem-like Cells

  • J Med Chem. 2024 Jun 13;67(11):9277-9301. doi: 10.1021/acs.jmedchem.4c00402.
Hua-Yu Wang  1 ,  Thu P Nguyen  1 ,  Alex C Sternisha  2 ,  Christopher L Carroll  1 ,  Bethany Cross  1 ,  Lorraine Morlock  1 ,  Noelle S Williams  1 ,  Samuel McBrayer  2 ,  Deepak Nijhawan  1  3 ,  Jef K De Brabander  1
Affiliations
  • 1. Department of Biochemistry, UT Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390, United States.
  • 2. Children's Medical Center Research Institute and Department of Pediatrics, UT Southwestern, 5323 Harry Hines Boulevard, Dallas, Texas 75390, United States.
  • 3. Department of Internal Medicine, Division of Hematology/Oncology and Program in Molecular Medicine, UT Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390, United States.
PMID: 38804887 DOI: 10.1021/acs.jmedchem.4c00402
Abstract

We recently discovered a novel N-aryl tetracyclic dicarboximide MM0299 (1) with robust activity against glioma stem-like cells that potently and selectively inhibits lanosterol synthase leading to the accumulation of the toxic shunt metabolite 24(S),25-epoxycholesterol. Herein, we delineate a systematic and comprehensive SAR study that explores the structural space surrounding the N-aryl tetracyclic dicarboximide scaffold. A series of 100 analogs were synthesized and evaluated for activity against the murine glioma stem-like cell line Mut6 and for metabolic stability in mouse liver S9 fractions. This study led to several analogs with single-digit nanomolar activity in Mut6 glioblastoma cells that were metabolically stable in S9 fractions. In vivo pharmacokinetic analysis of selected analogs identified compound 52a (IC50 = 63 nM; S9 T1/2 > 240 min) which was orally available (39% plasma; 58% brain) and displayed excellent brain exposure. Chronic oral dosing of 52a during a 2-week tolerability study indicated no adverse effect on body weight nor signs of hematologic, liver, or kidney toxicity.

Products