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: Lubomir L Vezenkov, Clément A Sanchez, Virginie Bellet, Vincent Martin, Marie Maynadier, Nadir Bettache, Vincent Lisowski, Jean Martinez, Marcel Garcia, Muriel Amblard, Jean-François Hernandez
• Journal: ChemMedChem (ChemMedChem) Vol. 11 Issue 3 Pg. 302-8 (Feb 04 2016) ISSN: 1860-7187 [Electronic] Germany
• PMID: 26639308 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Chemical References

• 2-aminomethylphenylacetic acid
• Amino Acids, Aromatic
• Antineoplastic Agents
• JMV4463
• Pepstatins
• Protease Inhibitors
• Cathepsin D

Topics

• Amino Acids, Aromatic (chemistry, pharmacology)
• Antineoplastic Agents (chemistry, pharmacology)
• Cathepsin D (antagonists & inhibitors)
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Dose-Response Relationship, Drug
• Drug Screening Assays, Antitumor
• Humans
• Molecular Conformation
• Pepstatins (chemistry, pharmacology)
• Protease Inhibitors (chemistry, pharmacology)
• Structure-Activity Relationship
• Tumor Cells, Cultured