Casein kinases as potential therapeutic targets

<b><i>Introduction:</i></b> The conventional term ‘casein kinase’ (CK) denotes three classes of kinases – CK1, CK2 and Golgi-CK (G-CK)/Fam20C (family with sequence similarity 20, member C) – sharing the ability to phoshorylate casein <i>in vitro,</i> but otherwise unrelated to each other. All CKs have been reported to be implicated in human diseases, and reviews individually dealing with the druggability of CK1 and CK2 are available. Our aim is to provide a comparative analysis of the three classes of CKs as therapeutic targets. <b><i>Areas covered:</i></b> CK2 is the CK for which implication in neoplasia is best documented, with the survival of cancer cells often relying on its overexpression. An ample variety of cell-permeable CK2 inhibitors have been developed, with a couple of these now in clinical trials. Isoform-specific CK1 inhibitors that are expected to play a beneficial role in oncology and neurodegeneration have been also developed. In contrast, the pathogenic potential of G-CK/Fam20C is caused by its loss of function. Activators of Fam20C, notably sphingolipids and their analogs, may prove beneficial in this respect. <b><i>Expert opinion:</i></b> Optimization of CK2 and CK1 inhibitors will prove useful to develop new therapeutic strategies for treating cancer and neurodegenerative disorders, while the design of potent activators of G-CK/Fam20C will provide a new tool in the fields of bio-mineralization and hypophosphatemic diseases.

<b><i>引言：</i></b> 常规术语"酪蛋白激酶（casein kinase，CK）"指代三类激酶：CK1、CK2以及高尔基酪蛋白激酶（Golgi-CK，G-CK）/序列相似性家族20成员C（family with sequence similarity 20, member C，Fam20C），三者均具备在体外磷酸化酪蛋白的能力，但彼此之间并无关联。已有研究表明所有酪蛋白激酶亚型均与人类疾病相关，且目前已有针对CK1和CK2成药性的专项综述发表。本综述旨在对这三类酪蛋白激酶作为治疗靶点的情况开展比较分析。
<b><i>论述范围：</i></b> CK2是目前在肿瘤发生中的作用被研究得最为透彻的酪蛋白激酶亚型，癌细胞的存活往往依赖于其过表达。目前已开发出多种具备细胞穿透性的CK2抑制剂，其中两款已进入临床试验阶段。此外，研究人员还开发出了亚型特异性的CK1抑制剂，有望在肿瘤治疗与神经退行性疾病治疗中发挥有益作用。与之相反，G-CK/Fam20C的致病机制源于其功能丧失。Fam20C的激活剂（尤其是鞘脂类及其类似物）有望在该领域发挥治疗益处。
<b><i>专家观点：</i></b> 优化CK2与CK1抑制剂将有助于开发治疗癌症及神经退行性疾病的全新治疗策略，而开发强效的G-CK/Fam20C激活剂则可为生物矿化与低磷酸盐血症相关疾病领域提供全新的研究工具。