Targeted Delivery of Cytotoxic NAMPT Inhibitors Using Antibody-Drug Conjugates
| Autor: | Julia H. Cochran, Paul G. Pittman, Steven Jin, Robert P. Lyon, Michelle Ulrich, Martha Anderson, Fu Li, Abbie Wong, Luke V. Loftus, Margo Zaval, Jay C. Nix, Jason Neale, Peter D. Senter, David W. Meyer, Jessica K. Simmons, Weiping Zeng, Andrew B. Waight, Christopher Scott Neumann, Kathleen C. Olivas |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Drug Cancer Research Immunoconjugates media_common.quotation_subject Cell Nicotinamide phosphoribosyltransferase Mice SCID Rats Sprague-Dawley 03 medical and health sciences chemistry.chemical_compound Structure-Activity Relationship Drug Delivery Systems Cell Line Tumor medicine Cytotoxic T cell Structure–activity relationship Animals Humans Enzyme Inhibitors Nicotinamide Phosphoribosyltransferase media_common chemistry.chemical_classification Cell Death Xenograft Model Antitumor Assays body regions 030104 developmental biology medicine.anatomical_structure Enzyme Oncology chemistry Cancer cell Cancer research Female NAD+ kinase |
| Zdroj: | Molecular cancer therapeutics. 17(12) |
| ISSN: | 1538-8514 |
| Popis: | Antibody–drug conjugates (ADCs) are a therapeutic modality that enables the targeted delivery of cytotoxic drugs to cancer cells. Identification of active payloads with unique mechanisms of action is a key aim of research efforts in the field. Herein, we report the development of inhibitors of nicotinamide phosphoribosyltransferase (NAMPT) as a novel payload for ADC technology. NAMPT is a component of a salvage biosynthetic pathway for NAD, and inhibition of this enzyme results in disruption of primary cellular metabolism leading to cell death. Through derivatization of the prototypical NAMPT inhibitor FK-866, we identified potent analogues with chemical functionality that enables the synthesis of hydrophilic enzyme-cleavable drug linkers. The resulting ADCs displayed NAD depletion in both cell-based assays and tumor xenografts. Antitumor efficacy is demonstrated in five mouse xenograft models using ADCs directed to indication-specific antigens. In rat toxicology models, a nonbinding control ADC was tolerated at >10-fold the typical efficacious dose used in xenografts. Moderate, reversible hematologic effects were observed with ADCs in rats, but there was no evidence for the retinal and cardiac toxicities reported for small-molecule inhibitors. These findings introduce NAMPT inhibitors as active and well-tolerated payloads for ADCs with promise to improve the therapeutic window of NAMPT inhibition and enable application in clinical settings. |
| Databáze: | OpenAIRE |
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