Centre for Drug Discovery and Development, Cancer Research Institute, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, South Australia 5001, Australia.
Med Chem. 2019;15(6):602-623. doi: 10.2174/1573406415666181219111511.
Aberrant expression of eukaryotic translation initiation factor 4E (eIF4E) is common in many types of cancer including acute myeloid leukaemia (AML). Phosphorylation of eIF4E by MAPK-interacting kinases (Mnks) is essential for the eIF4E-mediated oncogenic activity. As such, the pharmacological inhibition of Mnks can be an effective strategy for the treatment of cancer.
A series of N-phenyl-4-(1H-pyrrol-3-yl)pyrimidin-2-amine derivatives was designed and synthesised. The Mnk inhibitory activity of these derivatives as well as their anti-proliferative activity against MV4-11 AML cells was determined.
These compounds were identified as potent Mnk2 inhibitors. Most of them demonstrated potent anti-proliferative activity against MV4-11 AML cells. The cellular mechanistic studies of the representative inhibitors revealed that they reduced the level of phosphorylated eIF4E and induced apoptosis by down-regulating the anti-apoptotic protein myeloid cell leukaemia 1 (Mcl-1) and by cleaving poly(ADP-ribose)polymerase (PARP). The lead compound 7k possessed desirable pharmacokinetic properties and oral bioavailability.
This work proposes that exploration of the structural diversity in the context of Nphenyl- 4-(1H-pyrrol-3-yl)pyrimidin-2-amine would offer potent and selective Mnk inhibitors.
真核翻译起始因子 4E（eIF4E）的异常表达在包括急性髓系白血病（AML）在内的许多类型的癌症中很常见。MAPK 相互作用激酶（Mnks）对 eIF4E 的磷酸化对于 eIF4E 介导的致癌活性至关重要。因此，Mnks 的药理学抑制可能是治疗癌症的有效策略。
设计并合成了一系列 N-苯基-4-(1H-吡咯-3-基)嘧啶-2-胺衍生物。测定了这些衍生物对 Mnk 的抑制活性以及对 MV4-11 AML 细胞的抗增殖活性。
这些化合物被鉴定为有效的 Mnk2 抑制剂。它们中的大多数对 MV4-11 AML 细胞表现出很强的抗增殖活性。代表性抑制剂的细胞机制研究表明，它们通过下调抗凋亡蛋白髓细胞白血病 1（Mcl-1）和切割多聚（ADP-核糖）聚合酶（PARP）来降低磷酸化 eIF4E 的水平并诱导细胞凋亡。先导化合物 7k 具有良好的药代动力学性质和口服生物利用度。
这项工作表明，在 N-苯基-4-(1H-吡咯-3-基)嘧啶-2-胺的结构多样性方面进行探索将提供有效的、选择性的 Mnk 抑制剂。
