Gao Ling-Jie, Kovackova Sona, Sála Michal, Ramadori Anna Teresa, De Jonghe Steven, Herdewijn Piet
Rega Institute for Medical Research, Laboratory of Medicinal Chemistry, KU Leuven , Minderbroedersstraat 10, 3000 Leuven, Belgium.
J Med Chem. 2014 Sep 25;57(18):7624-43. doi: 10.1021/jm5007929. Epub 2014 Sep 11.
DRAK2 emerged as a promising drug target for the treatment of autoimmune diseases and to prevent graft rejection after organ transplantation. Screening of a compound library in a DRAK2 binding assay led to the identification of an isothiazolo[5,4-b]pyridine derivative as a novel ligand for DRAK2, displaying a Kd value of 1.6 μM. Subsequent medicinal chemistry work led to the discovery of a thieno[2,3-b]pyridine derivative with strong DRAK2 binding affinity (Kd = 9 nM). Moreover, this compound also behaves as a functional inhibitor of DRAK2 enzymatic activity, displaying an IC50 value of 0.82 μM, although lacking selectivity, when tested against DRAK1. This paper describes for the first time functionally active dual DRAK1 and DRAK2 inhibitors that can be used as starting point for the synthesis of chemical tool compounds to study DRAK1 and DRAK2 biology, or they can be considered as hit compounds for hit-to-lead optimization campaigns in drug discovery programs.
DRAK2成为治疗自身免疫性疾病和预防器官移植后移植物排斥反应的一个有前景的药物靶点。在DRAK2结合试验中对化合物库进行筛选，鉴定出一种异噻唑并[5,4-b]吡啶衍生物作为DRAK2的新型配体，其解离常数（Kd）值为1.6 μM。随后的药物化学研究发现了一种具有强DRAK2结合亲和力（Kd = 9 nM）的噻吩并[2,3-b]吡啶衍生物。此外，该化合物还表现为DRAK2酶活性的功能性抑制剂，在针对DRAK1进行测试时，其半数抑制浓度（IC50）值为0.82 μM，尽管缺乏选择性。本文首次描述了具有功能活性的DRAK1和DRAK2双重抑制剂，它们可作为合成化学工具化合物的起点，用于研究DRAK1和DRAK2生物学，或者可被视为药物发现项目中从苗头化合物到先导化合物优化过程的苗头化合物。
