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Published on: November 9, 2020
Design and synthesis of proteolysis targeting chimeras (PROTACs) as an EGFR degrader based on CO-1686
Qinlan Li1, Qian Guo1, Shuyi Wang1
1Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, PR China.
Abstract:
Epidermal growth factor receptor (EGFR) inhibitors represent the first-line treatment of non-small-cell lung cancer (NSCLC). However, the emergence of acquired drug resistance and side effects largely encumbered their application in clinic. The emerging technology proteolysis targeting chimera (PROTAC) could be an alternative strategy to overcome these problems. Herein, we reported the discovery of EGFRL858R/T790M degraders based on CO-1686. Promising PROTAC 1q could effectively and selectively inhibit the growth of PC-9 (EGFRDel 19) and H1975 (EGFRL858R/T790M) cells, but not that of A549 (EGFRWT) cells. In addition, 1q could time- and dose-dependently induce degradation of EGFRL858R/T790M in H1975 cells with a DC50 value of 355.9 nM, while did not show obvious effect on the EGFRDel 19 and EGFRWT protein. Preliminary mechanism study demonstrated that the protein degradation was mediated through ubiquitin-proteasome system (UPS). Furthermore, 1q could significantly induce the apoptosis of H1975 cells and arrest the cells in G0/G1 phase. These findings demonstrated that compound 1q could be used as initial lead compound for the development of new EGFRL858R/T790M degraders based therapy.
Insights
New proteolysis targeting chimera (PROTAC) compounds show promise in degrading epidermal growth factor receptor (EGFR) mutations in non-small-cell lung cancer (NSCLC). These novel EGFR degraders may overcome drug resistance and side effects associated with current treatments.
Area of Science:
- Oncology
- Molecular Biology
- Medicinal Chemistry
Background:
- Epidermal growth factor receptor (EGFR) inhibitors are first-line treatments for non-small-cell lung cancer (NSCLC).
- Acquired drug resistance and side effects limit the clinical efficacy of current EGFR inhibitors.
- Proteolysis targeting chimera (PROTAC) technology offers a novel strategy to overcome these limitations.
Purpose of the Study:
- To discover and characterize novel EGFR degraders based on the CO-1686 scaffold.
- To evaluate the efficacy and selectivity of a lead PROTAC compound (1q) against EGFR-mutated NSCLC cells.
- To investigate the mechanism of action and cellular effects of the identified EGFR degrader.
Main Methods:
- Synthesis of CO-1686-based PROTACs targeting EGFR.
- In vitro evaluation of cell growth inhibition in NSCLC cell lines with different EGFR mutations (PC-9, H1975, A549).
- Assessment of EGFR protein degradation, cell apoptosis, and cell cycle arrest.
- Ubiquitin-proteasome system (UPS) involvement analysis.
Main Results:
- PROTAC compound 1q effectively and selectively inhibited the growth of PC-9 (EGFRDel 19) and H1975 (EGFRL858R/T790M) cells.
- Compound 1q induced time- and dose-dependent degradation of EGFRL858R/T790M in H1975 cells (DC50 = 355.9 nM) via the UPS.
- 1q did not significantly affect EGFRDel 19 or wild-type EGFR (EGFRWT) protein levels and induced apoptosis and G0/G1 cell cycle arrest in H1975 cells.
Conclusions:
- Compound 1q is a promising initial lead for developing novel EGFRL858R/T790M degraders.
- PROTAC technology presents a viable strategy to overcome resistance and improve treatment outcomes in EGFR-mutated NSCLC.
- Further development of EGFR-targeting PROTACs could lead to more effective therapies for NSCLC patients.
