A deuterated analog of dasatinib disrupts cell cycle progression and displays anti-non-small cell lung cancer activity in vitro and in vivo

International Journal of Cancer. Journal International Du Cancer
Chunhua LingXinliang Mao

Abstract

The pan-Src family kinase inhibitor dasatinib has been approved for chronic myeloid leukemia treatment but displays limited activity in lung cancer patients. In this study, we used a deuterium substitution strategy to develop a class of novel chemicals based on dasatinib and found that these compounds maintain inhibition on c-Src activity and display anti-non-small cell lung cancer activity in vitro and in vivo. BRP800, one of these compounds, was chosen for further studies. BRP800 mainly displayed antiproliferative but not proapoptotic activity. Molecularly, BRP800 did not show significant effects on the expression of antiapoptotic genes, such as Bcl-2 and Mcl1, or on the activation of apoptotic enzymes, such as caspase-3, -8 or 9. However, BRP800 decreased expression of cell cycle promoting genes such as cyclins D1, D3, E, A and CDK4 and 6, and increased the expression of cell cycle negative regulators including p21, p27 and p53. Consistent with these findings, BRP800 arrested cells at the G0/G1 phase in a concentration-dependent manner, and the G0/G1 fraction was increased from 64% in control to 85% in BRP800-treated cells. We also evaluated the effects of BRP800 on NSCLC xenografts using H460 as a model in nude mice. Compar...Continue Reading

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Citations

Mar 13, 2014·Journal of Biochemical and Molecular Toxicology·Xin XuBiyin Cao
Feb 22, 2018·Organic & Biomolecular Chemistry·Yang GengYangjie Wu
Aug 18, 2017·Angewandte Chemie·Jens AtzrodtMarc Reid
Aug 12, 2015·Journal of Leukocyte Biology·Clara McClureMohamed El Gazzar
May 27, 2015·Journal of Labelled Compounds & Radiopharmaceuticals·Ruixue XuYuanwei Chen
Jul 2, 2016·Molecular Cancer Therapeutics·Rowan E MillerAlan Ashworth

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