TY - JOUR
T1 - Tumor-Activated Benzothiazole Inhibitors of Stearoyl-CoA Desaturase
AU - Williams, Noelle S.
AU - Gonzales, Stephen
AU - Naidoo, Jacinth
AU - Rivera-Cancel, Giomar
AU - Voruganti, Sukesh
AU - Mallipeddi, Prema
AU - Theodoropoulos, Panayotis C.
AU - Geboers, Sophie
AU - Chen, Hong
AU - Ortiz, Francisco
AU - Posner, Bruce
AU - Nijhawan, Deepak
AU - Ready, Joseph M.
N1 - Funding Information:
Financial support from the CPRIT (RP180457) and the Welch Foundation (I-1612 to J.M.R., I-1879 to D.N.) is acknowledged. We thank Emauela Copota for technical assistance.
Publisher Copyright:
Copyright © 2020 American Chemical Society.
PY - 2020/9/10
Y1 - 2020/9/10
N2 - 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.
AB - 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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U2 - 10.1021/acs.jmedchem.0c00899
DO - 10.1021/acs.jmedchem.0c00899
M3 - Article
C2 - 32787093
AN - SCOPUS:85090870438
SN - 0022-2623
VL - 63
SP - 9773
EP - 9786
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 17
ER -