Iegre Jessica, Brear Paul, De Fusco Claudia, Yoshida Masao, Mitchell Sophie L, Rossmann Maxim, Carro Laura, Sore Hannah F, Hyvönen Marko, Spring David R
Department of Chemistry , University of Cambridge , CB2 1EW , Cambridge , UK . Email:
Department of Biochemistry , University of Cambridge , CB2 1GA , Cambridge , UK . Email:
Chem Sci. 2018 Feb 20;9(11):3041-3049. doi: 10.1039/c7sc05122k. eCollection 2018 Mar 21.
CK2 is a critical cell cycle regulator that also promotes various anti-apoptotic mechanisms. Development of ATP-non-competitive inhibitors of CK2 is a very attractive strategy considering that the ATP binding site is highly conserved among other kinases. We have previously utilised a pocket outside the active site to develop a novel CK2 inhibitor, . Whilst bound to this new pocket it was also interacting with the ATP site: herein, we describe an example of a CK2α inhibitor that binds completely outside the active site. This second generation αD-site binding inhibitor, compound (IC = 7 μM, GI = 10.0 ± 3.6 μM), has numerous advantages over the previously reported , including a reduction in the number of rotatable bonds, the absence of amide groups susceptible to the action of proteases and improved cellular permeability. Unlike with , there was no need to facilitate cellular uptake by making a prodrug. Moreover, displayed no drop off between its ability to inhibit the kinase (IC) and the ability to inhibit cell proliferation (GI).
CK2是一种关键的细胞周期调节因子，它还能促进多种抗凋亡机制。考虑到ATP结合位点在其他激酶中高度保守，开发CK2的ATP非竞争性抑制剂是一种非常有吸引力的策略。我们之前利用活性位点之外的一个口袋开发了一种新型CK2抑制剂。当与这个新口袋结合时，它也与ATP位点相互作用：在此，我们描述了一种完全结合在活性位点之外的CK2α抑制剂的实例。这种第二代αD位点结合抑制剂，化合物（IC = 7 μM，GI = 10.0 ± 3.6 μM），与先前报道的相比有许多优点，包括可旋转键数量减少、不存在易受蛋白酶作用的酰胺基团以及细胞通透性提高。与不同的是，无需通过制备前药来促进细胞摄取。此外，在抑制激酶的能力（IC）和抑制细胞增殖的能力（GI）之间没有下降。
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