Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China.
Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang 110016, China.
J Med Chem. 2024 Sep 26;67(18):16248-16269. doi: 10.1021/acs.jmedchem.4c01096. Epub 2024 Sep 10.
Given the considerable potential of DOT1L inhibitors in lung cancer therapy and the problematic pharmacokinetics of nucleoside inhibitors, our group launched a development program of non-nucleoside DOT1L inhibitors to improve the pharmacokinetic properties. Herein, two series of non-nucleoside compounds bearing piperidine or 3-(aminomethyl)pyrrolidin-3-ol as "ribose mimics" were designed and evaluated through antiproliferation assay and western blot analysis. The optimal inhibited the proliferation of H460 cells with an IC value of 2.85 μM, about 13-fold more potent than SGC0946. Notably, demonstrated significant efficacy (TGI = 60.57%) in H460 cell-derived xenograft models and improved pharmacokinetic properties ( = 6.06 ± 2.94 h and CL = 55.18 ± 8.56 mL/kg/min). Moreover, a mechanism study validated that suppressed malignant phenotypes of lung cancer cells harboring R231Q mutation the MAPK/ERK signaling pathway. This work provides a promising molecule for lung cancer therapy in favor of clinical patients.
鉴于 DOT1L 抑制剂在肺癌治疗方面的巨大潜力，以及核苷抑制剂在药代动力学方面存在的问题，我们小组启动了一个非核苷 DOT1L 抑制剂的开发项目，以改善其药代动力学特性。在此，我们设计并评估了两个系列的非核苷化合物，它们分别以哌啶或 3-(氨甲基)吡咯烷-3-醇作为“核糖类似物”。通过增殖抑制实验和 Western blot 分析，我们发现优化后的化合物 对 H460 细胞的增殖具有抑制作用，IC 值为 2.85 μM，约比 SGC0946 强 13 倍。值得注意的是，化合物 在 H460 细胞来源的异种移植模型中表现出显著的疗效（TGI = 60.57%），并改善了药代动力学特性（ = 6.06 ± 2.94 h 和 CL = 55.18 ± 8.56 mL/kg/min）。此外，机制研究验证了 化合物通过抑制 MAPK/ERK 信号通路来抑制携带 R231Q 突变的肺癌细胞的恶性表型。这项工作为肺癌治疗提供了一个有前途的分子，有利于临床患者。
