From a novel HTS hit to potent, selective, and orally bioavailable KDM5 inhibitors
From a novel HTS hit to potent, selective, and orally bioavailable KDM5 inhibitors
复制标题
DOI：
10.1016/j.bmcl.2017.05.016
复制
发表时间：
2017-07-01
影响因子：
2.7
通讯作者：
Murray, Lesley
中科院分区：
文献类型：
--
作者：
Liang, Jun;Labadie, Sharada;Murray, Lesley
基因泰克/罗氏文库的高通量筛选（HTS）鉴定出一种新的、不带电的支架作为KDM5A抑制剂。由于缺乏对结合模式的了解，最初试图提高抑制剂效力的尝试未能提高效力，并且吡咯烷和吡啶之间存在C-C键进一步阻碍了类似物的合成。用C-N键代替它大大简化了合成，得到吡唑类似物35，我们得到了与KDM5A的共晶结构。使用基于结构的设计方法，我们确定了50个与原始命中相比具有改善的生化，细胞效力，降低的分子量和降低的亲脂性（LogD）。此外，50只小鼠的清除率低于9只小鼠。结合其在小鼠体内的血浆蛋白结合（PPB）非常低（40%），口服剂量为50 mg/kg，其未结合的C-max相当于其细胞效力的2倍（PC9 H3K4Me3 0.96 mu M），符合我们从新支架中提取的体内工具化合物的标准。(C) 2017 Elsevier Ltd.版权所有。
A high-throughput screening (HTS) of the Genentech/Roche library identified a novel, uncharged scaffold as a KDM5A inhibitor. Lacking insight into the binding mode, initial attempts to improve inhibitor potency failed to improve potency, and synthesis of analogs was further hampered by the presence of a C-C bond between the pyrrolidine and pyridine. Replacing this with a C-N bond significantly simplified synthesis, yielding pyrazole analog 35, of which we obtained a co-crystal structure with KDM5A. Using structure-based design approach, we identified 50 with improved biochemical, cell potency and reduced MW and lower lipophilicity (LogD) compared with the original hit. Furthermore, 50 showed lower clearance than 9 in mice. In combination with its remarkably low plasma protein binding (PPB) in mice (40%), oral dosing of 50 at 5 mg/kg resulted in unbound C-max similar to 2-fold of its cell potency (PC9 H3K4Me3 0.96 mu M), meeting our criteria for an in vivo tool compound from a new scaffold. (C) 2017 Elsevier Ltd. All rights reserved.