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Prodrug AST-003 Improves the Therapeutic Index of the Multi-Targeted Tyrosine Kinase Inhibitor Sunitinib

Patients have responded well to the multi-targeted tyrosine kinase inhibitor (TKI) Sunitinib in the clinic. But the severe toxic side effects associated with Sunitinib limit its therapeutic index. To improve the therapeutic index of Sunitinib, a prodrug strategy was employed to modify Sunitinib. The...

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Bibliographic Details
Published in:PloS one 2015-10, Vol.10 (10), p.e0141395
Main Authors: Huang, Qiang, Zhou, Changhua, Chen, Xiao, Dong, Bing, Chen, Siqi, Zhang, Ning, Liu, Yawei, Li, Anrong, Yao, Meicun, Miao, Ji, Li, Qing, Wang, Zhong
Format: Article
Language:English
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Summary:Patients have responded well to the multi-targeted tyrosine kinase inhibitor (TKI) Sunitinib in the clinic. But the severe toxic side effects associated with Sunitinib limit its therapeutic index. To improve the therapeutic index of Sunitinib, a prodrug strategy was employed to modify Sunitinib. The inactive prodrug AST-003 can be converted to Sunitinib in vitro and in vivo. Compared with Sunitinib, AST-003 has unique biochemical, cellular and pharmacokinetic properties with improved tolerability in mice and yield higher efficacy in tumor xenograft models. This prodrug strategy may constitute a novel paradigm to improve the therapeutic index of Sunitinib and other TKI or anti-angiogenesis drugs in general.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0141395