2. Academic Validation
  3. Tumor-Activated Benzothiazole Inhibitors of Stearoyl-CoA Desaturase

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

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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