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

• Published in: Journal of medicinal chemistry Vol. 67; no. 11; pp. 9277 - 9301
• Main Authors: Wang, Hua-Yu, Nguyen, Thu P., Sternisha, Alex C., Carroll, Christopher L., Cross, Bethany, Morlock, Lorraine, Williams, Noelle S., McBrayer, Samuel, Nijhawan, Deepak, De Brabander, Jef K.
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 13.06.2024; Amer Chemical Soc
• Subjects: Animals; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Brain Neoplasms - drug therapy; Brain Neoplasms - pathology; Cell Line, Tumor; Chemistry, Medicinal; Drug Discovery; Glioma - drug therapy; Glioma - pathology; Humans; Life Sciences & Biomedicine; Male; Mice; Neoplastic Stem Cells - drug effects; Pharmacology & Pharmacy; Science & Technology; Structure-Activity Relationship; LIVER X RECEPTORS; LIPID-METABOLISM; LIGANDS; 2,3-OXIDOSQUALENE CYCLASE INHIBITOR; PHARMACOLOGY; CHOLESTEROL-BIOSYNTHESIS; 24(S),25-EPOXYCHOLESTEROL; ATOM
• ISSN: 0022-2623; 1520-4804; 1520-4804
• DOI: 10.1021/acs.jmedchem.4c00402

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 T 1/2 > 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.