2‑Aminothiazole Derivatives as Selective Allosteric Modulators of the Protein Kinase CK2. 2. Structure-Based Optimization and Investigation of Effects Specific to the Allosteric Mode of Action

Protein
CK2 has gained much interest as an anticancer drug target
in the past decade. We had previously described the identification
of a new allosteric site on the catalytic α-subunit, along with
first small molecule ligands based on the 4-(4-phenylthiazol-2-ylamino)­benzoic
acid scaffold. In the present work, structure optimizations guided
by a binding model led to the identification of the lead compound
2-hydroxy-4-((4-(naphthalen-2-yl)­thiazol-2-yl)­amino)­benzoic
acid (27), showing a submicromolar potency against purified
CK2α (IC50 = 0.6 μM). Furthermore, 27 induced apoptosis and cell death in 786-O renal cell carcinoma cells
(EC50 = 5 μM) and inhibited STAT3 activation even
more potently than the ATP-competitive drug candidate CX-4945 (EC50 of 1.6 μM vs 5.3 μM). Notably, the potencies
of our allosteric ligands to inhibit CK2 varied depending on the individual
substrate. Altogether, the novel allosteric pocket was proved a druggable
site, offering an excellent perspective to develop efficient and selective
allosteric CK2 inhibitors.

近十年来，酪蛋白激酶2（CK2）作为抗肿瘤药物靶点受到广泛关注。此前我们已报道了催化α亚基（catalytic α-subunit）上全新别构位点（allosteric site）的发现，以及基于4-(4-苯基噻唑-2-基氨基)苯甲酸母核的首批小分子配体。本研究中，我们借助结合模型（binding model）指导结构优化，成功鉴定出先导化合物2-羟基-4-((4-(萘-2-基)噻唑-2-基)氨基)苯甲酸（编号27），其对纯化的CK2α展现出亚微摩尔级抑制活性（IC50=0.6μM）。此外，化合物27可诱导786-O肾癌细胞发生细胞凋亡与死亡（EC50=5μM），其对STAT3信号通路激活的抑制活性甚至优于ATP竞争性（ATP-competitive）候选药物CX-4945（二者EC50分别为1.6μM与5.3μM）。值得注意的是，我们开发的别构配体对CK2的抑制活性因所作用的底物（substrate）不同而存在差异。综上，本研究证实该全新别构口袋为可药用位点（druggable site），为开发高效且具有选择性的CK2别构抑制剂提供了极佳的研发前景。