Department of Experimental Biology, Faculty of Science, Masaryk University, 62500 Brno, Czech Republic.
TG Therapeutics, New York, NY 10014, USA.
Int J Mol Sci. 2020 Nov 27;21(23):9026. doi: 10.3390/ijms21239026.
The casein kinase 1 enzymes (CK1) form a family of serine/threonine kinases with seven CK1 isoforms identified in humans. The most important substrates of CK1 kinases are proteins that act in the regulatory nodes essential for tumorigenesis of hematological malignancies. Among those, the most important are the functions of CK1s in the regulation of Wnt pathways, cell proliferation, apoptosis and autophagy. In this review we summarize the recent developments in the understanding of biology and therapeutic potential of the inhibition of CK1 isoforms in the pathogenesis of chronic lymphocytic leukemia (CLL), other non-Hodgkin lymphomas (NHL), myelodysplastic syndrome (MDS), acute myeloid leukemia (AML) and multiple myeloma (MM). CK1δ/ε inhibitors block CLL development in preclinical models via inhibition of WNT-5A/ROR1-driven non-canonical Wnt pathway. While no selective CK1 inhibitors have reached clinical stage to date, one dual PI3Kδ and CK1ε inhibitor, umbralisib, is currently in clinical trials for CLL and NHL patients. In MDS, AML and MM, inhibition of CK1α, acting via activation of p53 pathway, showed promising preclinical activities and the first CK1α inhibitor has now entered the clinical trials.
酪蛋白激酶 1 酶（CK1）形成一组丝氨酸/苏氨酸激酶家族，在人类中已鉴定出 7 种 CK1 同工型。CK1 激酶最重要的底物是在血液恶性肿瘤发生的调节节点中起作用的蛋白质。其中，CK1 在调节 Wnt 通路、细胞增殖、凋亡和自噬中的功能最为重要。在这篇综述中，我们总结了 CK1 同工型抑制在慢性淋巴细胞白血病（CLL）、其他非霍奇金淋巴瘤（NHL）、骨髓增生异常综合征（MDS）、急性髓系白血病（AML）和多发性骨髓瘤（MM）发病机制中的生物学和治疗潜力的最新研究进展。CK1δ/ε 抑制剂通过抑制 WNT-5A/ROR1 驱动的非经典 Wnt 通路，在临床前模型中阻断 CLL 的发展。虽然迄今为止没有选择性 CK1 抑制剂达到临床阶段，但一种双重 PI3Kδ 和 CK1ε 抑制剂，即 umbralisib，目前正在 CLL 和 NHL 患者中进行临床试验。在 MDS、AML 和 MM 中，通过激活 p53 通路抑制 CK1α 表现出有前途的临床前活性，并且现在已经有一种 CK1α 抑制剂进入临床试验。
