1. Fragment-based identification of amides derived from trans-2-(pyridin-3-yl)cyclopropanecarboxylic acid as potent inhibitors of human nicotinamide phosphoribosyltransferase (NAMPT).
- Author
-
Giannetti AM, Zheng X, Skelton NJ, Wang W, Bravo BJ, Bair KW, Baumeister T, Cheng E, Crocker L, Feng Y, Gunzner-Toste J, Ho YC, Hua R, Liederer BM, Liu Y, Ma X, O'Brien T, Oeh J, Sampath D, Shen Y, Wang C, Wang L, Wu H, Xiao Y, Yuen PW, Zak M, Zhao G, Zhao Q, and Dragovich PS
- Subjects
- Amides chemistry, Amides pharmacology, Animals, Antineoplastic Agents chemistry, Antineoplastic Agents pharmacology, Cell Line, Tumor, Crystallography, X-Ray, Cyclopropanes chemistry, Cyclopropanes pharmacology, Drug Screening Assays, Antitumor, Heterografts, Humans, Mice, Mice, Nude, Models, Molecular, Neoplasm Transplantation, Protein Conformation, Pyridines chemistry, Pyridines pharmacology, Stereoisomerism, Structure-Activity Relationship, Sulfones chemistry, Sulfones pharmacology, Amides chemical synthesis, Antineoplastic Agents chemical synthesis, Cyclopropanes chemical synthesis, Nicotinamide Phosphoribosyltransferase antagonists & inhibitors, Pyridines chemical synthesis, Sulfones chemical synthesis
- Abstract
Potent, trans-2-(pyridin-3-yl)cyclopropanecarboxamide-containing inhibitors of the human nicotinamide phosphoribosyltransferase (NAMPT) enzyme were identified using fragment-based screening and structure-based design techniques. Multiple crystal structures were obtained of initial fragment leads, and this structural information was utilized to improve the biochemical and cell-based potency of the associated molecules. Many of the optimized compounds exhibited nanomolar antiproliferative activities against human tumor lines in in vitro cell culture experiments. In a key example, a fragment lead (13, KD = 51 μM) was elaborated into a potent NAMPT inhibitor (39, NAMPT IC50 = 0.0051 μM, A2780 cell culture IC50 = 0.000 49 μM) which demonstrated encouraging in vivo efficacy in an HT-1080 mouse xenograft tumor model.
- Published
- 2014
- Full Text
- View/download PDF