1. Targeted Delivery of Cytotoxic NAMPT Inhibitors Using Antibody-Drug Conjugates.
- Author
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Neumann CS, Olivas KC, Anderson ME, Cochran JH, Jin S, Li F, Loftus LV, Meyer DW, Neale J, Nix JC, Pittman PG, Simmons JK, Ulrich ML, Waight AB, Wong A, Zaval MC, Zeng W, Lyon RP, and Senter PD
- Subjects
- Animals, Cell Death drug effects, Cell Line, Tumor, Enzyme Inhibitors chemistry, Female, Humans, Immunoconjugates chemistry, Mice, SCID, Rats, Sprague-Dawley, Structure-Activity Relationship, Xenograft Model Antitumor Assays, Drug Delivery Systems, Enzyme Inhibitors administration & dosage, Enzyme Inhibitors pharmacology, Immunoconjugates pharmacology, Nicotinamide Phosphoribosyltransferase antagonists & inhibitors
- Abstract
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., (©2018 American Association for Cancer Research.)
- Published
- 2018
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