Van Dort Marcian E, McDonald Lucas, Jang Youngsoon, Heist Kevin, Bonham Christopher A, Abraskin Kamryn, Chenevert Thomas L, Ross Brian D
Center for Molecular Imaging, The University of Michigan Medical School, Ann Arbor, Michigan 48109, United States.
Department of Radiology, The University of Michigan Medical School, Ann Arbor, Michigan 48109, United States.
J Med Chem. 2025 Jun 12;68(11):11406-11418. doi: 10.1021/acs.jmedchem.5c00376. Epub 2025 May 16.
The mitogen-activated protein kinase (MAPK) and mechanistic target of rapamycin (mTOR) signaling nodes play a crucial role in many human cancers. Due to the molecular reciprocity between MAPK and mTOR signaling nodes, development of compounds with multikinase targeting was explored. A series of mTOR inhibitor analogs of AZD8055 and AZD2014 were designed to allow for covalent linking to a potent MAPK kinase (MEK) inhibitor to produce a single, bivalent chemical entity. Dual-acting agents (i.e., compound LP-65) were synthesized displaying high in vitro inhibition of both MEK (IC = 83.2 nM) and mTOR (IC = 40.5 nM). Additionally, compound LP-65 demonstrated significant modulation of MEK and mTOR signaling activity in human glioma cells (D54) and human melanoma cells (A375), with a corresponding decrease in cellular proliferation and migration. Treatment of mice with LP-65 (40 mg/kg) having a myeloproliferative neoplasm, myelofibrosis, revealed down modulation of in vivo signaling pathways and therapeutic efficacy.
丝裂原活化蛋白激酶（MAPK）和雷帕霉素机制性靶点（mTOR）信号节点在许多人类癌症中起着关键作用。由于MAPK和mTOR信号节点之间存在分子相互作用，因此探索了具有多激酶靶向性的化合物的开发。设计了一系列AZD8055和AZD2014的mTOR抑制剂类似物，以便与一种有效的丝裂原活化蛋白激酶（MEK）抑制剂进行共价连接，从而产生单一的二价化学实体。合成了双作用剂（即化合物LP-65），其在体外对MEK（IC = 83.2 nM）和mTOR（IC = 40.5 nM）均表现出高抑制作用。此外，化合物LP-65在人胶质瘤细胞（D54）和人黑色素瘤细胞（A375）中显示出对MEK和mTOR信号活性的显著调节作用，同时细胞增殖和迁移相应减少。用LP-65（40 mg/kg）治疗患有骨髓增殖性肿瘤、骨髓纤维化的小鼠，显示体内信号通路下调和治疗效果。
