Specific inhibition of CK2α from an anchor outside the active site.
Specific inhibition of CK2α from an anchor outside the active site.
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从活性位点外的一个锚定点对CK2α进行特异性抑制
DOI：
10.1039/c6sc02335e
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发表时间：
2016-11-01
期刊：
影响因子：
8.4
通讯作者：
Hyvönen M
中科院分区：
文献类型：
--
作者：
Brear P;De Fusco C;Hadje Georgiou K;Francis-Newton NJ;Stubbs CJ;Sore HF;Venkitaraman AR;Abell C;Spring DR;Hyvönen M
CAM 4066是一种特异性CK2α激酶抑制剂，锚定在活性位点外的隐蔽αD口袋中，并将“弹头”插入活性位点，阻断ATP结合，从而抑制激酶。由于ATP结合位点的显著保守性，蛋白激酶的选择性抑制剂的开发具有挑战性。在这里，我们描述了一种新的机制，通过这种机制，蛋白激酶CK 2 α可以使用ATP位点外的功能选择性抑制。我们发现了一个新的小分子结合位点，位于CK 2 α上，邻近ATP位点，位于αD环后面，称为αD口袋。锚定在该位点的一个精心制作的片段与ATP位点的一个低亲和力片段结合，产生了一种新型的选择性抑制剂（CAM 4066），其结合CK2α的Kd为320 nM，与其他CK2α抑制剂相比，其选择性显著提高。CAM 4066在几种细胞系中显示出靶向接合，并且与临床试验候选物CX 4945具有相似的效力。我们的数据表明，靶向保守性差的隐蔽口袋可以通过一种新的机制抑制CK2α，从而能够开发新一代选择性CK2α抑制剂。
CAM4066, a specific CK2α kinase inhibitor, is anchored in the cryptic αD pocket outside the active site and inserts a “warhead” into the active site, blocking ATP binding and thereby inhibiting the kinase. The development of selective inhibitors of protein kinases is challenging because of the significant conservation of the ATP binding site. Here, we describe a new mechanism by which the protein kinase CK2α can be selectively inhibited using features outside the ATP site. We have identified a new binding site for small molecules on CK2α adjacent to the ATP site and behind the αD loop, termed the αD pocket. An elaborated fragment anchored in this site has been linked with a low affinity fragment binding in the ATP site, creating a novel and selective inhibitor (CAM4066) that binds CK2α with a K d of 320 nM and shows significantly improved selectivity compared to other CK2α inhibitors. CAM4066 shows target engagement in several cell lines and similar potency to clinical trial candidate CX4945. Our data demonstrate that targeting a poorly conserved, cryptic pocket allows inhibition of CK2α via a novel mechanism, enabling the development of a new generation of selective CK2α inhibitors.