4LTS

Discovery of Potent and Efficacious Cyanoguanidine-containing Nicotinamide Phosphoribosyltransferase (Nampt) Inhibitors

4LTS の概要

• エントリーDOI: 10.2210/pdb4lts/pdb
• 関連するPDBエントリー: 4LWW
• 分子名称: Nicotinamide phosphoribosyltransferase, 2-cyano-1-pyridin-4-yl-3-(4-{[3-(trifluoromethoxy)phenyl]sulfonyl}benzyl)guanidine, PHOSPHATE ION, ... (5 entities in total)
• 機能のキーワード: transferase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Nucleus : P43490
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 115584.19

構造登録者

Zheng, X.,Baumeister, T.,Buckmelter, A.J.,Caligiuri, M.,Clodfelter, K.H.,Han, B.,Ho, Y.,Kley, N.,Lin, J.,Reynoids, D.J.,Sharma, G.,Smith, C.C.,Wang, Z.,Dragovich, P.S.,Oh, A.,Wang, W.,Zak, M.,Wang, L.,Yuen, P.,Bair, K.W. (登録日: 2013-07-23, 公開日: 2013-12-25, 最終更新日: 2023-09-20)

主引用文献

Zheng, X.,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.,Wang, Y.,Yuen, P.W.,Bair, K.W.
Discovery of potent and efficacious cyanoguanidine-containing nicotinamide phosphoribosyltransferase (Nampt) inhibitors.
Bioorg.Med.Chem.Lett., 24:337-343, 2014

PubMed Abstract: A co-crystal structure of amide-containing compound (4) in complex with the nicotinamide phosphoribosyltransferase (Nampt) protein and molecular modeling were utilized to design and discover a potent novel cyanoguanidine-containing inhibitor bearing a sulfone moiety (5, Nampt Biochemical IC50=2.5nM, A2780 cell proliferation IC50=9.7nM). Further SAR exploration identified several additional cyanoguanidine-containing compounds with high potency and good microsomal stability. Among these, compound 15 was selected for in vivo profiling and demonstrated good oral exposure in mice. It also exhibited excellent in vivo antitumor efficacy when dosed orally in an A2780 ovarian tumor xenograft model. The co-crystal structure of this compound in complex with the NAMPT protein was also determined.

PubMed: 24279990
DOI: 10.1016/j.bmcl.2013.11.006

実験手法

X-RAY DIFFRACTION (1.692 Å)