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Design, Synthesis, and Antitumor Activity Evaluation of Proteolysis-Targeting Chimeras as Degraders of Extracellular
Pengming Pan1, Yichao He1, Tongtong Geng1
1State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
Abstract:
Inhibition of the extracellular signal-regulated kinases 1/2 (ERK1/2) alone or in combination with other targets has emerged as a promising treatment strategy for a variety of human tumors. In addition to the development of inhibitors, the development of ERK1/2 degraders is an alternative approach to decrease its activity. We synthesized proteolysis-targeting chimeras (PROTACs) as effective ERK1/2 degraders, among which B1-10J showed high degradative activity, with DC50 of 102 nM and cytotoxic IC50 of 2.2 μM against HCT116 cells. Moreover, B1-10J dose-dependently inhibited tumor cell migration. Xenograft experiments in nude mice demonstrated that B1-10J inhibited HCT116 tumor cell growth and achieved significant regression of tumors at a daily dose of 25 mg/kg.
Insights
New proteolysis-targeting chimeras (PROTACs) effectively degrade extracellular signal-regulated kinases 1/2 (ERK1/2). The PROTAC B1-10J demonstrated potent anti-cancer activity, inhibiting tumor growth and migration in preclinical models.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Extracellular signal-regulated kinases 1/2 (ERK1/2) pathway dysregulation is implicated in various human cancers.
- Targeting ERK1/2 is a recognized strategy for cancer therapy.
- Developing degraders offers an alternative to inhibitors for reducing ERK1/2 activity.
Purpose of the Study:
- To synthesize and evaluate proteolysis-targeting chimeras (PROTACs) as novel ERK1/2 degraders.
- To assess the efficacy of a lead PROTAC compound, B1-10J, in preclinical cancer models.
Main Methods:
- Synthesis of PROTACs designed to induce degradation of ERK1/2.
- In vitro assessment of B1-10J's degradative activity (DC50) and cytotoxicity (IC50) in HCT116 cells.
- Evaluation of B1-10J's effect on tumor cell migration.
- In vivo efficacy study using HCT116 xenografts in nude mice.
Main Results:
- The PROTAC B1-10J exhibited potent ERK1/2 degradation with a DC50 of 102 nM.
- B1-10J displayed cytotoxic effects against HCT116 cells with an IC50 of 2.2 μM.
- B1-10J dose-dependently inhibited HCT116 cell migration.
- In vivo studies showed B1-10J inhibited tumor growth and induced significant tumor regression in HCT116 xenografts.
Conclusions:
- PROTACs represent a viable approach for targeting ERK1/2 in cancer.
- B1-10J is a potent ERK1/2 degrader with significant anti-tumor efficacy in vitro and in vivo.
- B1-10J warrants further investigation as a potential therapeutic agent for cancers driven by ERK1/2 signaling.
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