4KFN

Structure-Based Discovery of Novel Amide-Containing Nicotinamide Phosphoribosyltransferase (Nampt) Inhibitors

4KFN の概要

• エントリーDOI: 10.2210/pdb4kfn/pdb
• 関連するPDBエントリー: 4JR5 4KFO
• 分子名称: Nicotinamide phosphoribosyltransferase, N-[4-(piperidin-1-ylsulfonyl)benzyl]-1H-pyrrolo[3,2-c]pyridine-2-carboxamide, PHOSPHATE ION, ... (5 entities in total)
• 機能のキーワード: transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Cytoplasm (By similarity): P43490
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 115872.21

構造登録者

Zheng, X.,Bauer, P.,Baumeister, T.,Buckmelter, A.J.,Caligiuri, M.,Clodfelter, K.H.,Han, B.,Ho, Y.,Kley, N.,Lin, J.,Reynolds, D.J.,Sharma, G.,Smith, C.C.,Wang, Z.,Dragovich, P.S.,Gunzner-Toste, J.,Liederer, B.M.,Ly, J.,O'Brien, T.,Oh, A.,Wang, L.,Wang, W.,Xiao, Y.,Zak, M.,Zhao, G.,Yuen, P.,Bair, K.W. (登録日: 2013-04-27, 公開日: 2013-05-08, 最終更新日: 2024-02-28)

主引用文献

Zheng, X.,Bauer, P.,Baumeister, T.,Buckmelter, A.J.,Caligiuri, M.,Clodfelter, K.H.,Han, B.,Ho, Y.C.,Kley, N.,Lin, J.,Reynolds, D.J.,Sharma, G.,Smith, C.C.,Wang, Z.,Dragovich, P.S.,Oh, A.,Wang, W.,Zak, M.,Gunzner-Toste, J.,Zhao, G.,Yuen, P.W.,Bair, K.W.
Structure-based identification of ureas as novel nicotinamide phosphoribosyltransferase (nampt) inhibitors.
J.Med.Chem., 56:4921-4937, 2013

PubMed Abstract: Nicotinamide phosphoribosyltransferase (Nampt) is a promising anticancer target. Virtual screening identified a thiourea analogue, compound 5, as a novel highly potent Nampt inhibitor. Guided by the cocrystal structure of 5, SAR exploration revealed that the corresponding urea compound 7 exhibited similar potency with an improved solubility profile. These studies also indicated that a 3-pyridyl group was the preferred substituent at one inhibitor terminus and also identified a urea moiety as the optimal linker to the remainder of the inhibitor structure. Further SAR optimization of the other inhibitor terminus ultimately yielded compound 50 as a urea-containing Nampt inhibitor which exhibited excellent biochemical and cellular potency (enzyme IC50 = 0.007 μM; A2780 IC50 = 0.032 μM). Compound 50 also showed excellent in vivo antitumor efficacy when dosed orally in an A2780 ovarian tumor xenograft model (TGI of 97% was observed on day 17).

PubMed: 23617784
DOI: 10.1021/jm400186h

実験手法

X-RAY DIFFRACTION (1.6 Å)