title: A deuterated analog of dasatinib disrupts cell cycle progression and displays anti-non-small cell lung cancer activity in vitro and in vivo.
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. 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.
authors.affiliation: Department of Respiratory Diseases, the First Affiliated Hospital of Soochow University, Suzhou, China.
authors.forename: Chunhua
authors.initials: C
authors.lastname: Ling
authors.forename: Gang
authors.initials: G
authors.lastname: Chen
authors.forename: Guodong
authors.initials: G
authors.lastname: Chen
authors.forename: Zubin
authors.initials: Z
authors.lastname: Zhang
authors.forename: Biyin
authors.initials: B
authors.lastname: Cao
authors.forename: Kunkun
authors.initials: K
authors.lastname: Han
authors.forename: Jianming
authors.initials: J
authors.lastname: Yin
authors.forename: Alex
authors.initials: A
authors.lastname: Chu
authors.forename: Yun
authors.initials: Y
authors.lastname: Zhao
authors.forename: Xinliang
authors.initials: X
authors.lastname: Mao
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000378:metabolism*; D002453:Cell Cycle / Q000187:drug effects*; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D000069439:Dasatinib; D003903:Deuterium / Q000737:chemistry; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D011743:Pyrimidines / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D013844:Thiazoles / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays; D019061:src-Family Kinases / Q000037:antagonists & inhibitors
chemical_list: D000970:Antineoplastic Agents; C576675:BRP800; D011743:Pyrimidines; D013844:Thiazoles; D003903:Deuterium; D019061:src-Family Kinases; D000069439:Dasatinib