title: Prodrug AST-003 Improves the Therapeutic Index of the Multi-Targeted Tyrosine Kinase Inhibitor Sunitinib.
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.
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, China; Centre for Cellular & Structural Biology, Sun Yat-Sen University, Guangzhou, China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Huang
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, China; Centre for Cellular & Structural Biology, Sun Yat-Sen University, Guangzhou, China.
authors.forename: Changhua
authors.initials: C
authors.lastname: Zhou
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, China.
authors.forename: Xiao
authors.initials: X
authors.lastname: Chen
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, China; Centre for Cellular & Structural Biology, Sun Yat-Sen University, Guangzhou, China.
authors.forename: Bing
authors.initials: B
authors.lastname: Dong
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, China; Centre for Cellular & Structural Biology, Sun Yat-Sen University, Guangzhou, China.
authors.forename: Siqi
authors.initials: S
authors.lastname: Chen
authors.affiliation: Peking University Cancer Hospital, Beijing Institute for Cancer Research, Beijing, China.
authors.forename: Ning
authors.initials: N
authors.lastname: Zhang
authors.affiliation: Health Division of Guard Bureau, General Staff Department of PLA, Beijing, China.
authors.forename: Yawei
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Ascenta Pharmaceuticals, Guangzhou, Guangdong, P. R. China.
authors.forename: Anrong
authors.initials: A
authors.lastname: Li
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, China.
authors.forename: Meicun
authors.initials: M
authors.lastname: Yao
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, China.
authors.forename: Ji
authors.initials: J
authors.lastname: Miao
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, China; Centre for Cellular & Structural Biology, Sun Yat-Sen University, Guangzhou, China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Li
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, China; Centre for Cellular & Structural Biology, Sun Yat-Sen University, Guangzhou, China.
authors.forename: Zhong
authors.initials: Z
authors.lastname: Wang
mesh_terms: D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001565:Benzoates / Q000008:administration & dosage / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D004357:Drug Synergism; D004361:Drug Tolerance; D004950:Esterases / Q000378:metabolism; D005260:Female; D006801:Humans; D006868:Hydrolysis; D007211:Indoles / Q000008:administration & dosage / Q000494:pharmacology*; D051379:Mice; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D011355:Prodrugs / Q000008:administration & dosage / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011758:Pyrroles / Q000008:administration & dosage / Q000494:pharmacology*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D000077210:Sunitinib; D014018:Tissue Distribution; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: C000608436:AST-003; D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D001565:Benzoates; D007211:Indoles; D011355:Prodrugs; D047428:Protein Kinase Inhibitors; D011758:Pyrroles; D050796:STAT3 Transcription Factor; D051057:Proto-Oncogene Proteins c-akt; D004950:Esterases; D000077210:Sunitinib