title: Structure-Activity Relationships of JMV4463, a Vectorized Cathepsin D Inhibitor with Antiproliferative Properties: The Unique Role of the AMPA-Based Vector.
abstract: Cathepsin D (CathD) is overexpressed and secreted by several solid tumors and stimulates their growth, the mechanism of which is still not understood. In this context, the pepstatin bioconjugate JMV4463 [Ac-arg-O2 Oc-(Val)3-Sta-Ala-Sta-(AMPA)4-NH2; O2 Oc=8-amino-3,6-dioxaoctanoyl, Sta=statine, AMPA=ortho-aminomethylphenylacetyl], containing a new kind of cell-penetrating vector, was previously shown to exhibit potent antiproliferative effects in vitro and to delay the onset of tumors in vivo. In this study, we performed a structure-activity relationship analysis to evaluate the significance of the inhibitor and vector moieties of JMV4463. By modifying both statine residues of pepstatin we found that the antiproliferative activity is correlated with CathD inhibition, supporting a major role of the catalytic activity of intracellular CathD in cancer cell proliferation. Replacing the vector composed of four AMPA units with other vectors was found to abolish cytotoxicity, although all of the conjugates enabled pepstatin transport into cells. In addition, the AMPA4 vector must be localized at the C terminus of the bioconjugate. The unexpected importance of the vector structure and position for cytotoxic action suggests that AMPA4 enables pepstatin to inhibit the proteolysis of critical CathD substrates involved in cell proliferation via a unique mechanism of action.
authors.affiliation: Institut des Biomolécules Max Mousseron (IBMM), UMR5247 CNRS, Université de Montpellier, ENSCM, Faculté de Pharmacie, 15 avenue Charles Flahault, 34093, Montpellier Cedex 5, France.
authors.forename: Lubomir L
authors.initials: LL
authors.lastname: Vezenkov
authors.affiliation: Institut des Biomolécules Max Mousseron (IBMM), UMR5247 CNRS, Université de Montpellier, ENSCM, Faculté de Pharmacie, 15 avenue Charles Flahault, 34093, Montpellier Cedex 5, France.
authors.forename: Clément A
authors.initials: CA
authors.lastname: Sanchez
authors.affiliation: Institut des Biomolécules Max Mousseron (IBMM), UMR5247 CNRS, Université de Montpellier, ENSCM, Faculté de Pharmacie, 15 avenue Charles Flahault, 34093, Montpellier Cedex 5, France.
authors.forename: Virginie
authors.initials: V
authors.lastname: Bellet
authors.affiliation: Institut des Biomolécules Max Mousseron (IBMM), UMR5247 CNRS, Université de Montpellier, ENSCM, Faculté de Pharmacie, 15 avenue Charles Flahault, 34093, Montpellier Cedex 5, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Martin
authors.affiliation: Institut des Biomolécules Max Mousseron (IBMM), UMR5247 CNRS, Université de Montpellier, ENSCM, Faculté de Pharmacie, 15 avenue Charles Flahault, 34093, Montpellier Cedex 5, France.
authors.forename: Marie
authors.initials: M
authors.lastname: Maynadier
authors.affiliation: Institut des Biomolécules Max Mousseron (IBMM), UMR5247 CNRS, Université de Montpellier, ENSCM, Faculté de Pharmacie, 15 avenue Charles Flahault, 34093, Montpellier Cedex 5, France.
authors.forename: Nadir
authors.initials: N
authors.lastname: Bettache
authors.affiliation: Institut des Biomolécules Max Mousseron (IBMM), UMR5247 CNRS, Université de Montpellier, ENSCM, Faculté de Pharmacie, 15 avenue Charles Flahault, 34093, Montpellier Cedex 5, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Lisowski
authors.affiliation: Institut des Biomolécules Max Mousseron (IBMM), UMR5247 CNRS, Université de Montpellier, ENSCM, Faculté de Pharmacie, 15 avenue Charles Flahault, 34093, Montpellier Cedex 5, France.
authors.forename: Jean
authors.initials: J
authors.lastname: Martinez
authors.affiliation: Institut des Biomolécules Max Mousseron (IBMM), UMR5247 CNRS, Université de Montpellier, ENSCM, Faculté de Pharmacie, 15 avenue Charles Flahault, 34093, Montpellier Cedex 5, France.
authors.forename: Marcel
authors.initials: M
authors.lastname: Garcia
authors.affiliation: Institut des Biomolécules Max Mousseron (IBMM), UMR5247 CNRS, Université de Montpellier, ENSCM, Faculté de Pharmacie, 15 avenue Charles Flahault, 34093, Montpellier Cedex 5, France.
authors.forename: Muriel
authors.initials: M
authors.lastname: Amblard
authors.affiliation: Institut des Biomolécules Max Mousseron (IBMM), UMR5247 CNRS, Université de Montpellier, ENSCM, Faculté de Pharmacie, 15 avenue Charles Flahault, 34093, Montpellier Cedex 5, France. jean-francois.hernandez@univ-montp1.fr.
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Hernandez
mesh_terms: D024322:Amino Acids, Aromatic / Q000737:chemistry / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D002402:Cathepsin D / Q000037:antagonists & inhibitors*; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008968:Molecular Conformation; D010436:Pepstatins / Q000737:chemistry / Q000494:pharmacology*; D011480:Protease Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: C000611570:2-aminomethylphenylacetic acid; D024322:Amino Acids, Aromatic; D000970:Antineoplastic Agents; C587693:JMV4463; D010436:Pepstatins; D011480:Protease Inhibitors; D002402:Cathepsin D
keywords: antiproliferation; cathepsin D; cell-penetrating non-peptides; pepstatin delivery; structure-activity relationships