State Key Laboratory of Chemical Oncogenomics, Provincial Key Laboratory of Chemical Genomics, Engineering Laboratory for Chiral Drug Synthesis, School of Chemical Biology and Biotechnology, Shenzhen Graduate School, Peking University, Shenzhen, 518055, China.
State Key Laboratory of Chemical Oncogenomics, Provincial Key Laboratory of Chemical Genomics, Engineering Laboratory for Chiral Drug Synthesis, School of Chemical Biology and Biotechnology, Shenzhen Graduate School, Peking University, Shenzhen, 518055, China.
Eur J Med Chem. 2023 May 5;251:115236. doi: 10.1016/j.ejmech.2023.115236. Epub 2023 Mar 7.
Mitogen-activated protein kinase kinases 1/2 (MEK1/2) play critical roles in the canonical RAS/RAF/MEK/ERK pathway. Highly selective and potent non-ATP-competitive allosteric MEK1/2 inhibitors have been developed, and three of them were clinically approved for the treatment of BRAFV600 -mutant melanoma. However, the accompanying side effects of the systemically administered MEK1/2 drugs largely constrain their tolerable doses and efficacy. In this study, a series of mirdametinib-based optically activatable MEK1/2 inhibitors (opti-MEKi) were designed and synthesized. A structural-based design led to the discovery of photocaged compounds with dramatically diminished efficacy in vitro, whose activities can be spatiotemporally induced by short durations of irradiation of ultraviolet (365 nm) light. We demonstrated the robust photoactivation of MEK1/2 inhibition and antimelanoma activity in cultured human cells, as well as in a xenograft zebrafish model. Taken together, the modular approach presented herein provides a method for the optical control of MEK1/2 inhibitor activity, and these data support the further development of optically activatable agents for light-mediated antimelanoma phototherapy.
丝裂原活化蛋白激酶激酶 1/2（MEK1/2）在经典 RAS/RAF/MEK/ERK 通路中发挥着关键作用。已开发出高度选择性和强效的非 ATP 竞争性别构 MEK1/2 抑制剂，其中三种已被临床批准用于治疗 BRAFV600 突变型黑色素瘤。然而，全身性给予 MEK1/2 药物的伴随副作用在很大程度上限制了它们的耐受剂量和疗效。在这项研究中，设计并合成了一系列基于米尔德米替尼的光活化 MEK1/2 抑制剂（opti-MEKi）。基于结构的设计导致发现了体外效力大大降低的光封闭化合物，其活性可以通过短暂的紫外线（365nm）光照射来时空诱导。我们证明了 MEK1/2 抑制和抗黑色素瘤活性在培养的人类细胞以及异种移植斑马鱼模型中的强大光激活作用。总之，本文提出的模块化方法为 MEK1/2 抑制剂活性的光学控制提供了一种方法，这些数据支持进一步开发用于光介导的抗黑色素瘤光疗的光活化剂。
