在过去的十年中，Clk1已被确定为治疗各种疾病的有前途的靶点，其中非规则剪接发挥了一定作用。第一批针对Clk1的小分子已进入临床试验，用于治疗固体癌症，其中来自非规则剪接的致癌蛋白变异促进了肿瘤的进展。由于许多感染性病原体利用宿主细胞的剪接机器来确保有效复制，因此在这个领域的进一步适应症正在研究中，例如A型流感、HIV-1病毒和Trypanosoma感染，未来还可能发现更多的适应症。此外，发现Clk1通过导致tau剪接产物不平衡而有助于阿尔茨海默病的进展。有趣的是，纯合子Clk1敲除小鼠表现出相当温和的表型，与Clk1在非规则剪接中深刻的作用相比不符合预期。大多数Clk1抑制剂的主要缺点是它们的选择性不足；尤其是，Dyrk激酶和haspin经常被确认为副靶标，除了其他Clk isoform之外。仅有少数抑制剂显示出对Dyrk1A和haspin的选择性，而迄今为止还没有任何Clk1抑制剂能够对Clk4 isoform实现选择性。在本综述中，我们仔细汇编了来自科学文献的所有Clk1抑制剂，并总结了它们的结构活性关系（SAR）。此外，我们批判性地讨论了可用的选择性数据，并描述了抑制剂在细胞模型中的功效（如果有报道）。因此，我们提供了Clk1药物发现的当前状态的全面概述，并突出了最有前途的化学类型。©2022 Wiley Periodicals LLC。

Over the past decade, Clk1 has been identified as a promising target for the treatment of various diseases, in which deregulated alternative splicing plays a role. First small molecules targeting Clk1 are in clinical trials for the treatment of solid cancer, where variants of oncogenic proteins derived from alternative splicing promote tumor progression. Since many infectious pathogens hi-jack the host cell's splicing machinery to ensure efficient replication, further indications in this area are under investigation, such as Influenza A, HIV-1 virus, and Trypanosoma infections, and more will likely be discovered in the future. In addition, Clk1 was found to contribute to the progression of Alzheimer's disease through causing an imbalance of tau splicing products. Interestingly, homozygous Clk1 knockout mice showed a rather mild phenotype, opposed to what might be expected in view of the profound role of Clk1 in alternative splicing. A major drawback of most Clk1 inhibitors is their insufficient selectivity; in particular, Dyrk kinases and haspin were frequently identified as off-targets, besides the other Clk isoforms. Only few inhibitors were shown to be selective over Dyrk1A and haspin, whereas no Clk1 inhibitor so far achieved selectivity over the Clk4 isoform. In this review, we carefully compiled all Clk1 inhibitors from the scientific literature and summarized their structure-activity relationships (SAR). In addition, we critically discuss the available selectivity data and describe the inhibitor's efficacy in cellular models, if reported. Thus, we provide a comprehensive overview on the current state of Clk1 drug discovery and highlight the most promising chemotypes.© 2022 Wiley Periodicals LLC.