Tumor-Activated Benzothiazole Inhibitors of Stearoyl-CoA Desaturase

  • J Med Chem. 2020 Sep 10;63(17):9773-9786. doi: 10.1021/acs.jmedchem.0c00899.
Noelle S Williams  1 ,  Stephen Gonzales  1 ,  Jacinth Naidoo  1 ,  Giomar Rivera-Cancel  1  2 ,  Sukesh Voruganti  1 ,  Prema Mallipeddi  1 ,  Panayotis C Theodoropoulos  1  2 ,  Sophie Geboers  1 ,  Hong Chen  1 ,  Francisco Ortiz  1 ,  Bruce Posner  1 ,  Deepak Nijhawan  1  2 ,  Joseph M Ready  1
Affiliations
  • 1. Department of Biochemistry, UT Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, Texas 75390-9038, United States.
  • 2. Department of Internal Medicine, Division of Hematology and Oncology, UT Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, Texas 75390-9038, United States.
PMID: 32787093 DOI: 10.1021/acs.jmedchem.0c00899
Abstract

A series of N-acyl benzothiazoles shows selective and potent cytotoxicity against Cancer cell lines expressing Cytochrome P450 4F11. A prodrug form is metabolized by Cancer cells into an active inhibitor of stearoyl-CoA desaturase (SCD). Substantial variation on the acyl portion of the inhibitors allowed the identification of (R)-27, which balanced potency, solubility, and lipophilicity to allow proof-of-concept studies in mice. The prodrugs were activated inside the tumor, where they can arrest tumor growth. Together, these observations offer promise that a tumor-activated prodrug strategy might exploit the essentiality of SCD for tumor growth, while avoiding toxicity associated with systemic SCD inhibition.

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