Department of Pharmacology, School of Medical Sciences, University of Sydney, NSW 2006, Australia.
MIMR-PHI Institute of Medical Research, 27-31 Wright Street, Clayton, VIC 3168, Australia; Monash University, Wellington Road, Clayton, VIC 3800, Australia.
Pharmacol Ther. 2015 Jul;151:87-98. doi: 10.1016/j.pharmthera.2015.03.004. Epub 2015 Mar 17.
Protein kinases are one of the most studied drug targets in current pharmacological research, as evidenced by the vast number of kinase-targeting agents enrolled in active clinical trials. Dual-specificity Tyrosine phosphorylation-Regulated Kinase 1A (DYRK1A) has been much less studied compared to many other kinases. DYRK1A primary function occurs during early development, where this protein regulates cellular processes related to proliferation and differentiation of neuronal progenitor cells. Although most extensively characterised for its role in brain development, DYRK1A is over-expressed in a variety of diseases including a number of human malignancies, such as haematological and brain cancers. Here we review the accumulating molecular studies that support our understanding of how DYRK1A signalling could underlie these pathological functions. The relevance of DYRK1A in a number of diseases is also substantiated with intensive drug discovery efforts to develop potent and selective inhibitors of DYRK1A. Several classes of DYRK1A inhibitors have recently been disclosed and some molecules are promising leads to develop DYRK1A inhibitors as drugs for DYRK1A-dependent diseases.
蛋白激酶是当前药理学研究中研究最多的药物靶点之一，这从大量正在进行的临床研究中就可以看出。与许多其他激酶相比，双特异性酪氨酸磷酸化调节激酶 1A（DYRK1A）的研究要少得多。DYRK1A 的主要功能发生在早期发育过程中，该蛋白调节与神经元祖细胞增殖和分化相关的细胞过程。尽管 DYRK1A 因其在大脑发育中的作用而被广泛研究，但它在多种疾病中过度表达，包括许多人类恶性肿瘤，如血液和脑癌。在这里，我们回顾了越来越多的分子研究，这些研究支持了我们对 DYRK1A 信号如何为这些病理功能提供基础的理解。DYRK1A 在许多疾病中的相关性也得到了强化，因为人们正在进行密集的药物发现工作，以开发有效的、选择性的 DYRK1A 抑制剂。最近已经披露了几类 DYRK1A 抑制剂，一些分子作为 DYRK1A 依赖性疾病的 DYRK1A 抑制剂具有很大的发展潜力。
