2. Academic Validation
  3. Optically activated MEK1/2 inhibitors (Opti-MEKi) as potential antimelanoma agents

Optically activated MEK1/2 inhibitors (Opti-MEKi) as potential antimelanoma agents

  • Eur J Med Chem. 2023 May 5:251:115236. doi: 10.1016/j.ejmech.2023.115236.
Chenzhou Hao 1,  Xiaofeng Li 1,  Zhunchao Wang 1,  Lihong Liu 1,  Fengli He 1,  Zhengying Pan 2
Affiliations

Affiliations

  • 1 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.
  • 2 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. Electronic address: [email protected].
PMID: 36924668 DOI: 10.1016/j.ejmech.2023.115236
Abstract

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.

Keywords

Allosteric inhibitor; Antimelanoma agent; MEK1/2; Optically activatable inhibitor; Phototherapy.

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