Changhua Zhou¹, Qiang Huang¹, Xiao Chen¹, Bing Dong¹, Siqi Chen¹, Ning Zhang², Yawei Liu³, Anrong Li⁴, Meicun Yao¹, Qing Li¹, Zhong Wang¹

¹School of Pharmaceutical Sciences, Sun Yat-Sen University, ²Beijing Institute for Cancer Research, Peking University Cancer Hospital, ³General Staff Department of PLA, Health Division of Guard Bureau, ⁴Ascenta Pharmaceuticals, Ascenta Pharmaceuticals

Objective:As a potent angiogenesis inhibitor, Sunitinib has shown good response in clinic. However, severe toxic side effects limit its efficacy. To improve the therapeutic index of Sunitinib, an esterase based pro-drug strategy was employed. Method: An esterase based pro-drug strategy was used to modify Sunitinib, and pro-drug stability in plasma was analysed. The in vitro activity of pro-drug was evaluated using biochemical assays. MTD assay and antitumor activity of pro-drug AST003 were performed in vivo. Result: Pro-drugs can be hydrolyzed. Pro-drugs inhibit RTK activity and tumor cell proliferation. The inactive pro-drug AST-003 can be converted to Sunitinib in vitro and in vivo. AST003 has less systemic toxicities than Sunitinib in mice, and has higher efficacy in tumor xenograft model.Conclusion: AST 003 has unique biochemical, cellular and pharmacokinetic properties, which lead AST-003 to be more tolerated in mice, yet yield higher efficacy than Sunitinib in tumor xenograft models. This strategy may present a novel paradigm to improve the therapeutic index of Sunitinib and other anti-angiogenesis drugs.

Key Words: Sunitinib  AST003  therapeutic index