Nicotinamide-Ponatinib Analogues as Potent Anti-CML and Anti-AML Compounds
Nicotinamide-Ponatinib Analogues as Potent Anti-CML and Anti-AML Compounds
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DOI：
10.1021/acsomega.9b03223
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发表时间：
2020-02-18
期刊：
影响因子：
4.1
通讯作者：
Sintim, Herman O.
中科院分区：
文献类型：
--
作者：
Larocque, Elizabeth;Chu, Elizabeth Fei Yin;Sintim, Herman O.
Ponatinib是一种多激酶抑制剂，用于治疗ABL1（T315I）激酶突变的慢性髓性白血病患者。由于FLT3、RET和成纤维细胞生长因子受体（FGFRs）的有效抑制，它也被用于评估急性髓性白血病（AML）、胆道和肺癌。波纳替尼的多激酶抑制特性也可以解释其毒性，因此具有改善激酶选择性或不同激酶抑制特性的类似物可能具有更好的耐受性。将氮引入到药物化合物中可以提高疗效和药物特性（一个称为“必要氮”的概念）。在这里，我们引入额外的氮到ponatinib的苯酰胺部分，以得到烟酰胺类似物。ponatinib的烟酰胺类似物HSN748保留对FLT3、ABL1、RET和PDGFR α / β的活性，但失去对c-Src和P38 α的活性。MNK1和2是磷酸化eIF4E以调节蛋白质翻译复合体的关键激酶。MNK也调节mTORC1信号传导并促进雷帕霉素耐药。MNK1和2抑制剂正在被评估用于抗癌治疗。Ponatinib不是MNK1或2的有效抑制剂，但烟酰胺类似物是MNKs的有效抑制剂。这有力地证明了氮的概念对于改变药物的效力和选择性是必要的。
Ponatinib is a multikinase inhibitor that is used to treat chronic myeloid leukemia patients harboring mutated ABL1(T315I) kinase. Due to the potent inhibition of FLT3, RET, and fibroblast growth factor receptors (FGFRs), it is also being evaluated against acute myeloid leukemia (AML), biliary, and lung cancers. The multikinase inhibition profile of ponatinib may also account for its toxicity, thus analogs with improved kinase selectivity or different kinase inhibition profiles could be better tolerated. The introduction of nitrogen into drug compounds can enhance efficacy and drug properties (a concept called "necessary nitrogen"). Here, we introduce additional nitrogen into the benzamide moiety of ponatinib to arrive at nicotinamide analogs. A nicotinamide analogue of ponatinib, HSN748, retains activity against FLT3, ABL1, RET, and PDGFR alpha/beta but loses activity against c-Src and P38 alpha. MNK1 and 2 are key kinases that phosphorylate eIF4E to regulate the protein translation complex. MNK also modulates mTORC1 signaling and contributes to rapamycin resistance. Inhibitors of MNK1 and 2 are being evaluated for anticancer therapy. Ponatinib is not a potent inhibitor of MNK1 or 2, but the nicotinamide analogs are potent inhibitors of MNKs. This illustrates a powerful demonstration of the necessary nitrogen concept to alter both the potency and selectivity of drugs.