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PLoS One. 2015 Oct 29;10(10):e0141395. doi: 10.1371/journal.pone.0141395. eCollection 2015.

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

Author information

1
School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, China; Centre for Cellular & Structural Biology, Sun Yat-Sen University, Guangzhou, China.
2
School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, China.
3
Peking University Cancer Hospital, Beijing Institute for Cancer Research, Beijing, China.
4
Health Division of Guard Bureau, General Staff Department of PLA, Beijing, China.
5
Ascenta Pharmaceuticals, Guangzhou, Guangdong, P. R. China.

Abstract

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.

PMID:
26513662
PMCID:
PMC4626378
DOI:
10.1371/journal.pone.0141395
[Indexed for MEDLINE]
Free PMC Article

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