title: Folate-vinca alkaloid conjugates for cancer therapy: a structure-activity relationship.
abstract: Vintafolide is a potent folate-targeted vinca alkaloid small molecule drug conjugate (SMDC) that has shown promising results in multiple clinical oncology studies. Structurally, vintafolide consists of 4 essential modules: (1) folic acid, (2) a hydrophilic peptide spacer, (3) a disulfide-containing, self-immolative linker, and (4) the cytotoxic drug, desacetylvinblastine hydrazide (DAVLBH). Here, we report a structure-activity study evaluating the biological impact of (i) substituting DAVLBH within the vintafolide molecule with other vinca alkaloid analogues such as vincristine, vindesine, vinflunine, or vinorelbine; (ii) substituting the naturally (S)-configured Asp-Arg-Asp-Asp-Cys peptide with alternative hydrophilic spacers of varied composition; and (iii) varying the composition of the linker module. A series of vinca alkaloid-containing SMDCs were synthesized and purified by HPLC and LCMS. The SMDCs were screened in vitro against folate receptor (FR)-positive cells, and anti-tumor activity was tested against well-established subcutaneous FR-positive tumor xenografts. The cytotoxic and anti-tumor activity was directly compared to that produced by vintafolide. Among all the folate vinca alkaloid SMDCs tested, DAVLBH-containing SMDCs were active, while those constructed with vincristine, vindesine, or vinorelbine analogues failed to produce meaningful biological activity. Within the DAVLBH series, having a bioreleasable, self-immolative linker system was found to be critical for activity since multiple analogues constructed with thioether-based linkers all failed to produce meaningful activity both in vitro and in vivo. Substitutions of some or all of the natural amino acids within vintafolide's hydrophilic spacer module did not significantly change the in vitro or in vivo potency of the SMDCs. Vintafolide remains one of the most potent folate-vinca alkaloid SMDCs produced to date, and continued clinical development is warranted.
authors.affiliation: Endocyte, Inc. , 300 Kent Avenue, West Lafayette, Indiana 47906, United States.
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Leamon
authors.forename: Iontcho R
authors.initials: IR
authors.lastname: Vlahov
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Reddy
authors.forename: Marilynn
authors.initials: M
authors.lastname: Vetzel
authors.forename: Hari Krishna R
authors.initials: HK
authors.lastname: Santhapuram
authors.forename: Fei
authors.initials: F
authors.lastname: You
authors.forename: Alicia
authors.initials: A
authors.lastname: Bloomfield
authors.forename: Ryan
authors.initials: R
authors.lastname: Dorton
authors.forename: Melissa
authors.initials: M
authors.lastname: Nelson
authors.forename: Paul
authors.initials: P
authors.lastname: Kleindl
authors.forename: Jeremy F
authors.initials: JF
authors.lastname: Vaughn
authors.forename: Elaine
authors.initials: E
authors.lastname: Westrick
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D005260:Female; D005492:Folic Acid / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008968:Molecular Conformation; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000473:pathology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014748:Vinca Alkaloids / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D014748:Vinca Alkaloids; D005492:Folic Acid