Nicotinamide-Ponatinib Analogues as Potent Anti-CML and Anti-AML Compounds.,ACS Omega

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Nicotinamide-Ponatinib Analogues as Potent Anti-CML and Anti-AML Compounds.
ACS Omega ( IF 3.7 ) Pub Date : 2020-02-04 , DOI: 10.1021/acsomega.9b03223
Elizabeth Larocque ₁ , Elizabeth Fei Yin Chu ₁ , Nimmashetti Naganna ₁ , Herman O Sintim _{1,

2,

3}

Affiliation

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 PDGFRα/β but loses activity against c-Src and P38α. 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.

中文翻译：

烟酰胺-帕纳替尼类似物作为有效的抗 CML 和抗 AML 化合物。

Ponatinib 是一种多激酶抑制剂，用于治疗携带突变 ABL1(T315I) 激酶的慢性粒细胞白血病患者。由于对 FLT3、RET 和成纤维细胞生长因子受体 (FGFR) 的有效抑制作用，它也正在针对急性髓性白血病 (AML)、胆道癌和肺癌进行评估。普纳替尼的多激酶抑制特性也可能解释其毒性，因此具有改善的激酶选择性或不同激酶抑制特性的类似物可以更好地耐受。将氮引入药物化合物中可以增强功效和药物特性（称为“必需氮”的概念）。在这里，我们将额外的氮引入到普纳替尼的苯甲酰胺部分中以获得烟酰胺类似物。 ponatinib 的烟酰胺类似物 HSN748 保留针对 FLT3、ABL1、RET 和 PDGFRα/β 的活性，但失去针对 c-Src 和 P38α 的活性。 MNK1 和 2 是磷酸化 eIF4E 以调节蛋白质翻译复合物的关键激酶。 MNK 还调节 mTORC1 信号传导并导致雷帕霉素耐药。 MNK1 和 2 抑制剂正在评估其抗癌治疗效果。 Ponatinib 不是 MNK1 或 2 的有效抑制剂，但烟酰胺类似物是 MNK 的有效抑制剂。这有力地证明了改变药物效力和选择性所必需的氮概念。

更新日期：2020-02-18

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