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Design, Synthesis, and Biological Evaluation of Proteolysis-Targeting Chimeras as Highly Selective and Efficient
Pengming Pan1, Tongtong Geng1, Zhongtang Li1
1State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
Abstract:
Extracellular signal-regulated kinase 5 (ERK5) is recognized as a key member of the mitogen-activated protein kinase family and is involved in tumor growth, migration, and angiogenesis. However, the results of ERK5 inhibition in multiple studies are controversial, and a highly specific ERK5-targeting agent is required to confirm physiological functions. Using proteolysis-targeting chimera technology, we designed the selective ERK5 degrader PPM-3 and examined its biological effect on cancer cells. Interestingly, the selective degradation of ERK5 with PPM-3 did not influence tumor cell growth directly. Based on proteomics analysis, the ERK5 deletion may be associated with tumor immunity. PPM-3 influences tumor development by affecting the differentiation of macrophages. Therefore, PPM-3 is an effective small-molecule tool for studying ERK5 and a promising immunotherapy drug candidate.
Insights
A novel tool, PPM-3, selectively degrades Extracellular signal-regulated kinase 5 (ERK5) without impacting tumor cell growth. This discovery reveals ERK5’s role in tumor immunity by influencing macrophage differentiation, positioning PPM-3 as a potential immunotherapy candidate.
Area of Science:
- Molecular Biology
- Cancer Research
- Immunology
Background:
- Extracellular signal-regulated kinase 5 (ERK5) is a mitogen-activated protein kinase implicated in tumor progression.
- Previous studies on ERK5 inhibition have yielded controversial results, highlighting the need for specific targeting agents.
- Understanding ERK5's precise role in cancer requires precise molecular tools.
Purpose of the Study:
- To design and evaluate a selective ERK5 degrader using proteolysis-targeting chimera (PROTAC) technology.
- To investigate the biological effects of selective ERK5 degradation on cancer cells.
- To explore the potential of the designed degrader as a tool for studying ERK5 and as an immunotherapy candidate.
Main Methods:
- Design and synthesis of a selective ERK5 degrader, PPM-3, utilizing proteolysis-targeting chimera technology.
- Assessment of PPM-3's effect on cancer cell growth and proliferation.
- Proteomics analysis to identify downstream effects of ERK5 degradation.
- Investigation of PPM-3's impact on macrophage differentiation and tumor immunity.
Main Results:
- Selective degradation of ERK5 by PPM-3 did not directly inhibit cancer cell growth.
- Proteomics data suggested a link between ERK5 depletion and tumor immunity.
- PPM-3 was found to modulate tumor development by influencing macrophage differentiation.
- PPM-3 demonstrated efficacy in affecting tumor immunity.
Conclusions:
- PPM-3 is a highly specific small-molecule tool for the selective degradation of ERK5.
- ERK5 plays a role in tumor immunity through its influence on macrophage differentiation.
- PPM-3 shows promise as a potential candidate for cancer immunotherapy.
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