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A deuterated analog of dasatinib disrupts cell cycle progression and displays anti‐non‐small cell lung cancer activity in vitro and in vivo
Author(s) -
Ling Chunhua,
Chen Gang,
Chen Guodong,
Zhang Zubin,
Cao Biyin,
Han Kunkun,
Yin Jianming,
Chu Alex,
Zhao Yun,
Mao Xinliang
Publication year - 2012
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.27504
Subject(s) - dasatinib , cancer research , in vivo , cell cycle , cell growth , docetaxel , cell cycle checkpoint , chemistry , pharmacology , apoptosis , biology , cancer , medicine , myeloid leukemia , biochemistry , imatinib , microbiology and biotechnology
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. Compared with the known NSCLC drug docetaxel, BRP800 displayed potent and similar antitumor activity but with less toxicity. These findings suggest that the deuterated analog of dasatinib is antiproliferative by inhibiting c‐Src and disrupting cell cycle progression, and could be further developed as a novel drug for non‐small lung cancer treatment.