PO.ET01.04 · 实验与分子治疗
开发吡啶并嘧啶衍生物KC12作为选择性双重Pim/Mnk抑制剂以抑制白血病细胞生长
Development of the pyridopyrimidine derivative KC12 as a selective dual Pim/Mnk inhibitor to inhibit leukemia cell growth
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摘要 Abstract
中文摘要
髓系白血病是一种异常增殖性疾病，依赖于快速的帽依赖性蛋白翻译。Maloney鼠白血病病毒前病毒整合（Pim）激酶和丝裂原激活蛋白激酶相互作用激酶（Mnk）在激活帽依赖性翻译中均发挥关键作用，使它们成为抗癌药物开发的有吸引力的靶点。尽管几种选择性Pim或Mnk抑制剂已进入临床试验，但其疗效有限。我们提出，同时抑制Pim/Mnk两种激酶对于有效治疗是必需的。此前，我们报道了首个双重Pim和Mnk抑制剂21o，其具有吡啶并[3,2-d]嘧啶核心（IC50 Mnk1：9 nM，Mnk2：5 nM，Pim1：120 nM），但存在溶解性差的问题。我们基于分子对接对21o进行了优化，获得了化合物KC12，其激酶抑制活性增强（IC50 Mnk1：32 nM，Mnk2：3 nM；Pim1：32 nM），选择性提高（在100 nM时，42种受测激酶中仅4种显示>40%抑制）。与21o以及Pim抑制剂TP-3654和Mnk抑制剂eFT508相比，KC12表现出更高的水溶性和更优的抗增殖活性。KC12在K562细胞中诱导G0/G1期细胞周期停滞，在MOLM-13细胞中诱导凋亡，这与eIF4E和4EBP1磷酸化的抑制以及帽依赖性翻译产物c-Myc和Mcl-1的抑制相关。此外，KC12表现出比21o更有利的药代动力学特征，并在MOLM-13异种移植模型中表现出增强的抗肿瘤疗效。这些发现表明，KC12作为一种新型、强效且选择性的双重Pim/Mnk抑制剂，值得作为治疗药物进一步开发。
查看英文原文 English abstract
Myeloid leukemia is an abnormal proliferative disease relying on fast cap-dependent protein translation. Both provirus integration in Maloney murine leukemia virus (Pim) kinases and mitogen-activated protein kinase-interacting kinases (Mnk) play key roles in activating cap-dependent translation, making them attractive targets for anticancer drug development. Although several selective Pim or Mnk inhibitors entered clinical trials, their efficacy was limited. We propose that concurrent inhibition of both Pim/Mnk kinases is necessary for effective treatment. Previously, we reported the first dual Pim and Mnk inhibitor 21o with a pyrido[3,2- d ]pyrimidine core (IC 50 Mnk1: 9 nM, Mnk2: 5 nM, Pim1: 120 nM), but suffered from poor solubility. We optimized 21o based on molecular docking and obtained a compound KC12 with enhanced kinase inhibitory activity (IC 50 Mnk1:32 nM, Mnk2 3 nM; Pim 1 32 nM) and improved selectivity (only 4 out of 42 tested kinases showed >40% inhibition at 100 nM). KC12 exhibits increased aqueous solubility and superior anti-proliferative activity compared to 21o, as well as to the Pim inhibitor TP-3654 and the Mnk inhibitor eFT508. KC12 induced G0/G1 phase cell cycle arrest in K562 cells and apoptosis in MOLM-13 cells, correlated to the suppression of both eIF4E and 4EBP1 phosphorylation, and the cap-dependent translation products c-Myc and Mcl-1. Moreover, KC12 demonstrated a more favorable pharmacokinetic profile than 21o and exhibited enhanced antitumor efficacy in MOLM-13 xenograft models. These findings suggest that KC12 acts as a novel, potent, and selective dual Pim/Mnk inhibitor and is worthy of further development as a therapeutic agent.
利益披露 Disclosure
L. Zhao, None..
K. Xing, None..
J. Zhang, None..
S. Zuo, None..
F. Zhang, None..
S. Waxman, None..
Y. Jing, None.