基于表型筛选的烟酰胺磷酸核糖转移酶（NAMPT）抑制剂的结构设计
Structure based design of nicotinamide phosphoribosyltransferase (NAMPT) inhibitors from a phenotypic screen.
作者信息
Palacios Daniel S, Meredith Erik, Kawanami Toshio, Adams Christopher, Chen Xin, Darsigny Veronique, Geno Erin, Palermo Mark, Baird Daniel, Boynton Geoffrey, Busby Scott A, George Elizabeth L, Guy Chantale, Hewett Jeffrey, Tierney Laryssa, Thigale Sachin, Weihofen Wilhelm, Wang Louis, White Nicole, Yin Ming, Argikar Upendra A
机构信息
Global Discovery Chemistry, Novartis Institute for Biomedical Research, 22 Windsor Street, Cambridge, MA 02139, USA.
Global Discovery Chemistry, Novartis Institute for Biomedical Research, 22 Windsor Street, Cambridge, MA 02139, USA.
出版信息
Bioorg Med Chem Lett. 2018 Feb 1;28(3):365-370. doi: 10.1016/j.bmcl.2017.12.037. Epub 2017 Dec 18.
Nicotinamide phosphoribosyltransferase is a key metabolic enzyme that is a potential target for oncology. Utilizing publicly available crystal structures of NAMPT and in silico docking of our internal compound library, a NAMPT inhibitor, 1, obtained from a phenotypic screening effort was replaced with a more synthetically tractable scaffold. This compound then provided an excellent foundation for further optimization using crystallography driven structure based drug design. From this approach, two key motifs were identified, the (S,S) cyclopropyl carboxamide and the (S)-1-N-phenylethylamide that endowed compounds with excellent cell based potency. As exemplified by compound 27e such compounds could be useful tools to explore NAMPT biology in vivo.
烟酰胺磷酸核糖转移酶是一种关键的代谢酶，是肿瘤学的潜在靶点。利用公开可得的烟酰胺磷酸核糖转移酶晶体结构以及我们内部化合物库的计算机对接技术，从表型筛选工作中获得的一种烟酰胺磷酸核糖转移酶抑制剂1，被一个更易于合成的骨架所取代。然后，该化合物为使用基于晶体学驱动的结构药物设计进行进一步优化提供了良好基础。通过这种方法，确定了两个关键基序，即(S,S)环丙基甲酰胺和(S)-1-N-苯乙酰胺，这些基序赋予化合物优异的基于细胞的活性。以化合物27e为例，这类化合物可能是在体内探索烟酰胺磷酸核糖转移酶生物学特性的有用工具。
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