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

Qiang Huang; Changhua Zhou; Xiao Chen; Bing Dong; Siqi Chen; Ning Zhang; Yawei Liu; Anrong Li; Meicun Yao; Ji Miao; Qing Li; Zhong Wang

doi:10.1371/journal.pone.0141395

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

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

Authors

Qiang Huang¹, Changhua Zhou¹, Xiao Chen², Bing Dong¹, Siqi Chen¹, Ning Zhang³, Yawei Liu⁴, Anrong Li⁵, Meicun Yao², Ji Miao², Qing Li¹, Zhong Wang¹

Affiliations

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Angiogenesis Inhibitors / administration & dosage
Angiogenesis Inhibitors / pharmacology*
Animals
Antineoplastic Agents / administration & dosage
Antineoplastic Agents / pharmacology*
Benzoates / administration & dosage
Benzoates / pharmacology*
Cell Line, Tumor
Cell Proliferation / drug effects
Disease Models, Animal
Drug Synergism
Drug Tolerance
Esterases / metabolism
Female
Humans
Hydrolysis
Indoles / administration & dosage
Indoles / pharmacology*
Mice
Neoplasms / drug therapy
Neoplasms / metabolism
Neoplasms / pathology
Phosphorylation / drug effects
Prodrugs / administration & dosage
Prodrugs / pharmacology*
Protein Kinase Inhibitors / administration & dosage
Protein Kinase Inhibitors / pharmacology*
Proto-Oncogene Proteins c-akt / metabolism
Pyrroles / administration & dosage
Pyrroles / pharmacology*
STAT3 Transcription Factor / metabolism
Sunitinib
Tissue Distribution
Tumor Burden / drug effects
Xenograft Model Antitumor Assays

Substances

AST-003
Angiogenesis Inhibitors
Antineoplastic Agents
Benzoates
Indoles
Prodrugs
Protein Kinase Inhibitors
Pyrroles
STAT3 Transcription Factor
Proto-Oncogene Proteins c-akt
Esterases
Sunitinib

Grants and funding

This work received financial support from the Introduced Innovative R&D Team Leadership of Guangdong Province (P.R. China) (2011Y038) to Qing Li and Zhong Wang. The funder provided support in the form of partial salaries for authors Miao J, Li Q, and Wang Z, and research materials. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.