Tang Jiawei, Xie Youquan, Huang Jingxun, Zhang Liao, Jiang Weiye, Li Zhiyu, Bian Jinlei
Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, People's Republic of China.
Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, People's Republic of China.
Bioorg Med Chem. 2022 Sep 15;70:116921. doi: 10.1016/j.bmc.2022.116921. Epub 2022 Jul 9.
90% of genes in the human body undergo alternative splicing (AS) after transcription, which enriches protein species and regulates protein levels. However, there is growing evidence that various genetic isoforms resulting from dysregulated alternative splicing are prevalent in various types of cancers. Dysregulated alternative splicing leads to cancer generation and maintenance of cancer properties such as proliferation differentiation, apoptosis inhibition, invasion metastasis, and angiogenesis. Serine/arginine-rich proteins and SR protein-associated kinases mediate splice site recognition and splice complex assembly during variable splicing. Based on the impact of dysregulated alternative splicing on disease onset and progression, the search for small molecule inhibitors targeting alternative splicing is imminent. In this review, we discuss the structure and specific biological functions of SR proteins and describe the regulation of SR protein function by SR protein related kinases meticulously, which are closely related to the occurrence and development of various types of cancers. On this basis, we summarize the reported small molecule inhibitors targeting SR proteins and SR protein related kinases from the perspective of medicinal chemistry. We mainly categorize small molecule inhibitors from four aspects, including targeting SR proteins, targeting Serine/arginine-rich protein-specific kinases (SRPKs), targeting Cdc2-like kinases (CLKs) and targeting dual-specificity tyrosine-regulated kinases (DYRKs), in terms of structure, inhibition target, specific mechanism of action, biological activity, and applicable diseases. With this review, we are expected to provide a timely summary of recent advances in alternative splicing regulated by kinases and a preliminary introduction to relevant small molecule inhibitors.
人体中90%的基因在转录后会发生可变剪接（AS），这丰富了蛋白质种类并调节蛋白质水平。然而，越来越多的证据表明，由失调的可变剪接产生的各种基因异构体在各种类型的癌症中普遍存在。失调的可变剪接导致癌症的发生并维持癌症的特性，如增殖分化、凋亡抑制、侵袭转移和血管生成。富含丝氨酸/精氨酸的蛋白质和SR蛋白相关激酶在可变剪接过程中介导剪接位点识别和剪接复合体组装。基于失调的可变剪接对疾病发生和进展的影响，寻找靶向可变剪接的小分子抑制剂迫在眉睫。在这篇综述中，我们讨论了SR蛋白的结构和特定生物学功能，并详细描述了SR蛋白相关激酶对SR蛋白功能的调节，这些与各种类型癌症的发生和发展密切相关。在此基础上，我们从药物化学的角度总结了已报道的靶向SR蛋白和SR蛋白相关激酶的小分子抑制剂。我们主要从四个方面对小分子抑制剂进行分类，包括靶向SR蛋白、靶向富含丝氨酸/精氨酸蛋白特异性激酶（SRPKs）、靶向Cdc2样激酶（CLKs）和靶向双特异性酪氨酸调节激酶（DYRKs），涉及结构、抑制靶点、具体作用机制、生物学活性和适用疾病。通过这篇综述，我们期望及时总结激酶调节的可变剪接的最新进展，并对相关小分子抑制剂进行初步介绍。
