Dragovich Peter S, Zhao Guiling, Baumeister Timm, Bravo Brandon, Giannetti Anthony M, Ho Yen-Ching, Hua Rongbao, Li Guangkun, Liang Xiaorong, Ma Xiaolei, O'Brien Thomas, Oh Angela, Skelton Nicholas J, Wang Chengcheng, Wang Weiru, Wang Yunli, Xiao Yang, Yuen Po-wai, Zak Mark, Zhao Qiang, Zheng Xiaozhang
Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
Bioorg Med Chem Lett. 2014 Feb 1;24(3):954-62. doi: 10.1016/j.bmcl.2013.12.062. Epub 2013 Dec 21.
The fragment-based identification of two novel and potent biochemical inhibitors of the nicotinamide phosphoribosyltransferase (NAMPT) enzyme is described. These compounds (51 and 63) incorporate an amide moiety derived from 3-aminopyridine, and are thus structurally distinct from other known anti-NAMPT agents. Each exhibits potent inhibition of NAMPT biochemical activity (IC50=19 and 15 nM, respectively) as well as robust antiproliferative properties in A2780 cell culture experiments (IC50=121 and 99 nM, respectively). However, additional biological studies indicate that only inhibitor 51 exerts its A2780 cell culture effects via a NAMPT-mediated mechanism. The crystal structures of both 51 and 63 in complex with NAMPT are also independently described.
本文描述了基于片段筛选鉴定出的两种新型且强效的烟酰胺磷酸核糖转移酶（NAMPT）生化抑制剂。这些化合物（51和63）含有源自3-氨基吡啶的酰胺部分，因此在结构上与其他已知的抗NAMPT药物不同。在A2780细胞培养实验中，每种化合物都表现出对NAMPT生化活性的强效抑制作用（IC50分别为19和15 nM）以及强大的抗增殖特性（IC50分别为121和99 nM）。然而，进一步的生物学研究表明，只有抑制剂51通过NAMPT介导的机制发挥其在A2780细胞培养中的作用。本文还分别描述了51和63与NAMPT复合物的晶体结构。
