Bioorganic & Medicinal Chemistry Letters ( IF 2.5 ) Pub Date : 2020-07-31 , DOI: 10.1016/j.bmcl.2020.127456
Zhengnian Li 1 , Chelsea E Powell 1 , Brian J Groendyke 1 , Thomas W Gero 1 , Frederic Feru 1 , John Feutrill 2 , Bailing Chen 2 , Bin Li 2 , Hilary Szabo 3 , Nathanael S Gray 1 , David A Scott 1
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The protein kinase TNK2 (ACK1) is an emerging drug target for a variety of indications, in particular for cancer where it plays a key role transmitting cell survival, growth and proliferative signals via modification of multiple downstream effectors by unique tyrosine phosphorylation events. Scaffold morphing based on our previous TNK2 inhibitor XMD8-87 identified urea 17 from which we developed the potent and selective compound 32. A co-crystal structure was obtained showing 32 interacting primarily with the main chain atoms of an alanine residue of the hinge region. Additional H-bonds exist between the urea NHs and the Thr205 and Asp270 residues.
中文翻译：
通过支架变形发现了一系列苯并嘧啶基二氮杂庚酮TNK2抑制剂。
蛋白激酶TNK2（ACK1）是各种适应症的新兴药物靶标，尤其是对于癌症，在该疾病中，它通过独特的酪氨酸磷酸化事件修饰多个下游效应子，在传递细胞存活，生长和增殖信号中起关键作用。基于我们以前的TNK2抑制剂XMD8-87的支架变形确定了尿素17，我们从中开发出了有效的选择性化合物32。获得共晶体结构，其显示32个主要与铰链区的丙氨酸残基的主链原子相互作用。尿素NH与Thr205和Asp270残基之间还存在其他H键。
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