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PLoS One. 2019 Mar 25;14(3):e0205623. doi: 10.1371/journal.pone.0205623. eCollection 2019.

Targeting mitochondria in cancer therapy could provide a basis for the selective anti-cancer activity.

Author information

1
Department of Molecular and Medical Genetics, Knight Cancer Institute, Oregon Health and Science University, Portland, Oregon, United States of America.
2
Q-MOL LLC, San Diego, California, United States of America.
3
Medicinal Chemistry Core, Oregon Health and Science University, Portland, Oregon, United States of America.
4
Chemistry Department, Portland State University, Portland, Oregon, United States of America.
5
Department of Biomedical Engineering, Oregon Health and Science University, Portland, Oregon, United States of America.
6
Department of Cell, Developmental and Cancer Biology, Oregon Health and Science University, Portland, Oregon, United States of America.
7
Howard Hughes Medical Institute, Portland, Oregon, United States of America.
8
Division of Hematology & Medical Oncology, Oregon Health & Science University, Portland, Oregon, United States of America.

Abstract

To determine the target of the recently identified lead compound NSC130362 that is responsible for its selective anti-cancer efficacy and safety in normal cells, structure-activity relationship (SAR) studies were conducted. First, NSC13062 was validated as a starting compound for the described SAR studies in a variety of cell-based viability assays. Then, a small library of 1,4-naphthoquinines (1,4-NQs) and quinoline-5,8-diones was tested in cell viability assays using pancreatic cancer MIA PaCa-2 cells and normal human hepatocytes. The obtained data allowed us to select a set of both non-toxic compounds that preferentially induced apoptosis in cancer cells and toxic compounds that induced apoptosis in both cancer and normal cells. Anti-cancer activity of the selected non-toxic compounds was confirmed in viability assays using breast cancer HCC1187 cells. Consequently, the two sets of compounds were tested in multiple cell-based and in vitro activity assays to identify key factors responsible for the observed activity. Inhibition of the mitochondrial electron transfer chain (ETC) is a key distinguishing activity between the non-toxic and toxic compounds. Finally, we developed a mathematical model that was able to distinguish these two sets of compounds. The development of this model supports our conclusion that appropriate quantitative SAR (QSAR) models have the potential to be employed to develop anti-cancer compounds with improved potency while maintaining non-toxicity to normal cells.

PMID:
30908483
PMCID:
PMC6433232
DOI:
10.1371/journal.pone.0205623
[Indexed for MEDLINE]
Free PMC Article

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