Discovery of a Potent BTK Inhibitor with a Novel Binding Mode by Using Parallel Selections with a DNA-Encoded Chemical Library
Discovery of a Potent BTK Inhibitor with a Novel Binding Mode by Using Parallel Selections with a DNA-Encoded Chemical Library
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DOI：
10.1002/cbic.201600573
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发表时间：
2017-05-04
期刊：
影响因子：
3.2
通讯作者：
Clark, Matthew A.
中科院分区：
文献类型：
--
作者：
Cuozzo, John W.;Centrella, Paolo A.;Clark, Matthew A.
我们已经通过使用多个平行选择条件，包括靶浓度的变化和添加已知结合剂以提供竞争信息，从超过1.1亿个化合物的单个DNA编码文库中鉴定并表征了布鲁顿酪氨酸激酶（BTK）的新型有效抑制剂。通过比较在这些条件下的文库构建块组合的富集，观察到不同的结合谱;一种仅在高浓度的BTK下富集并且与ATP竞争，另一种在高浓度和低浓度的BTK下富集并且不与ATP竞争。代表后一种特征的化合物在生物化学和细胞BTK测定中显示出低纳摩尔效力。动力学作用机制研究的结果与选择特征一致。对最有效化合物的共晶体结构的分析表明了一种新的结合模式，揭示了BTK中的新口袋。我们的研究结果表明，基于配置文件的选择策略，使用DNA编码的库形成了一种新的方法的基础，以快速识别小分子抑制剂与新的结合模式，以临床相关的目标。
We have identified and characterized novel potent inhibitors of Bruton's tyrosine kinase (BTK) from a single DNA-encoded library of over 110 million compounds by using multiple parallel selection conditions, including variation in target concentration and addition of known binders to provide competition information. Distinct binding profiles were observed by comparing enrichments of library building block combinations under these conditions; one enriched only at high concentrations of BTK and was competitive with ATP, and another enriched at both high and low concentrations of BTK and was not competitive with ATP. A compound representing the latter profile showed low nanomolar potency in biochemical and cellular BTK assays. Results from kinetic mechanism of action studies were consistent with the selection profiles. Analysis of the co-crystal structure of the most potent compound demonstrated a novel binding mode that revealed a new pocket in BTK. Our results demonstrate that profile-based selection strategies using DNA-encoded libraries form the basis of a new methodology to rapidly identify small molecule inhibitors with novel binding modes to clinically relevant targets.