| Autor: |
Giannetti AM; Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States., 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, Dragovich PS |
| Jazyk: |
angličtina |
| Zdroj: |
Journal of medicinal chemistry [J Med Chem] 2014 Feb 13; Vol. 57 (3), pp. 770-92. Date of Electronic Publication: 2014 Jan 22. |
| DOI: |
10.1021/jm4015108 |
| Abstrakt: |
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. |
| Databáze: |
MEDLINE |
| Externí odkaz: |
|
