Larocque Elizabeth, Chu Elizabeth Fei Yin, Naganna Nimmashetti, Sintim Herman O
Department of Chemistry, Purdue University, 560 Oval Drive, West Lafayette, Indiana 47907, United States.
Institute for Drug Discovery, Purdue University, 720 Clinic Drive, West Lafayette, Indiana 47907, United States.
ACS Omega. 2020 Feb 4;5(6):2690-2698. doi: 10.1021/acsomega.9b03223. eCollection 2020 Feb 18.
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.
波纳替尼是一种多激酶抑制剂，用于治疗携带突变型ABL1（T315I）激酶的慢性髓性白血病患者。由于其对FLT3、RET和成纤维细胞生长因子受体（FGFRs）有强效抑制作用，它也正在被评估用于治疗急性髓性白血病（AML）、胆管癌和肺癌。波纳替尼的多激酶抑制谱也可能是其毒性的原因，因此具有改善的激酶选择性或不同激酶抑制谱的类似物可能具有更好的耐受性。在药物化合物中引入氮可以提高疗效和药物性质（这一概念称为“必需氮”）。在此，我们在波纳替尼的苯甲酰胺部分引入额外的氮，得到烟酰胺类似物。波纳替尼的一种烟酰胺类似物HSN748保留了对FLT3、ABL1、RET和PDGFRα/β的活性，但失去了对c-Src和P38α的活性。MNK1和2是将eIF4E磷酸化以调节蛋白质翻译复合物的关键激酶。MNK还调节mTORC1信号传导并导致对雷帕霉素耐药。MNK1和2的抑制剂正在接受抗癌治疗评估。波纳替尼不是MNK1或2的强效抑制剂，但烟酰胺类似物是MNK的强效抑制剂。这有力地证明了必需氮概念可改变药物的效力和选择性。
