School of Chemistry and Materials Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, 1 Sub-lane Xiangshan, Hangzhou, 310024, China.
State Key Laboratory of Chemical Biology, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 345 Lingling Road, Shanghai, 200032, China.
Commun Biol. 2024 Jun 18;7(1):742. doi: 10.1038/s42003-024-06455-4.
Aminoacyl-tRNA synthetases (aaRSs) play a central role in the translation of genetic code, serving as attractive drug targets. Within this family, the lysyl-tRNA synthetase (LysRS) constitutes a promising antimalarial target. ASP3026, an anaplastic lymphoma kinase (ALK) inhibitor was recently identified as a novel Plasmodium falciparum LysRS (PfLysRS) inhibitor. Here, based on cocrystal structures and biochemical experiments, we developed a series of ASP3026 analogues to improve the selectivity and potency of LysRS inhibition. The leading compound 36 showed a dissociation constant of 15.9 nM with PfLysRS. The inhibitory efficacy on PfLysRS and parasites has been enhanced. Covalent attachment of L-lysine to compound 36 resulted in compound 36K3, which exhibited further increased inhibitory activity against PfLysRS but significantly decreased activity against ALK. However, its inhibitory activity against parasites did not improve, suggesting potential future optimization directions. This study presents a new example of derivatization of kinase inhibitors repurposed to inhibit aaRS.
氨酰-tRNA 合成酶（aaRSs）在遗传密码的翻译中起着核心作用，是有吸引力的药物靶点。在这个家族中，赖氨酸-tRNA 合成酶（LysRS）是一个很有前途的抗疟靶点。最近，一种间变性淋巴瘤激酶（ALK）抑制剂 ASP3026 被鉴定为新型疟原虫 LysRS（PfLysRS）抑制剂。在这里，基于共晶结构和生化实验，我们开发了一系列 ASP3026 类似物，以提高 LysRS 抑制的选择性和效力。先导化合物 36 对 PfLysRS 的解离常数为 15.9 nM。PfLysRS 和寄生虫的抑制效果得到了增强。将 L-赖氨酸共价连接到化合物 36 上得到化合物 36K3，其对 PfLysRS 的抑制活性进一步增强，但对 ALK 的活性显著降低。然而，它对寄生虫的抑制活性并没有提高，这表明了潜在的未来优化方向。本研究提供了一个将激酶抑制剂衍生化用于抑制 aaRS 的新范例。
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