PROTAC Targeting EGFR

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As a leading CRO in targeted protein degradation, BOC Sciences provides one-stop EGFR PROTACs design services to meet our clients' new drug discovery goals. Epidermal growth factor receptor (EGFR) proteolysis targeting chimera (PROTAC) is one type of compound that targets and degrades target proteins in view of the cells’ own ubiquitin proteasome system (UPS). PROTAC targeting EGFR is formed by a bifunctional chimeric small molecule to bind the E3 ubiquitin ligase and the ligand of EGFR in the meantime, so that the target protein is ubiquitinated and labeled. After that, it enters the proteasome pathway for degradation.

Introduction

EGFR is a receptor for epithelial growth factor cell proliferation and signaling. It is a kind of glycoprotein and belongs to tyrosine kinase type receptor. It has a cell membrane penetration and a molecular weight of 170 kda. EGFR is located on the surface of cell membrane and activated by binding with ligands which is linked to tumor cell proliferation, angiogenesis and so on. EGFR tyrosine kinase inhibitor (TKI) not only blocks the EGFR pathway in tumors, but also blocks the EGFR pathway in the skin and gastrointestinal tract, and causes related adverse events. Furthermore, it is prone to drug resistance. The principle of action of EGFR-TKI is to inhibit the production of proteins, while the principle of action of EGFR PROTAC is to send these proteins into the proteasome for complete degradation while breaking the definition of traditional drugs.

About EGFR PROTACs

First, EGFR PROTAC needs to form a ternary complex which requires the simultaneous binding of PROTAC with protein of interest (in this case EGFR) and E3 ubiquitin ligase. At one end of EGFR PROTAC, the linker is covalently linked to the ligand of EGFR (e.g. EGFR-TKI). At the other end, the linker binds to the ligand of E3 ubiquitin ligase, such as the von Hippel−Lindau (VHL) ligand. Subsequent ubiquitination is essential for degradation EGFR, and proteasomes are involved in the degradation process. Synthetic EGFR PROTAC can penetrate the cell membrane and induce the degradation of EGFR at low concentrations.

Compared with the traditional EGFR-TKI, EGFR PROTAC has two main advantages.

• EGFR PROTAC possesses catalytic degradation function. The degradation of target proteins by PROTAC is a catalytic process, which can be recycled and reused. This property makes it possible to produce activity at a lower dose.
• EGFR PROTAC can overcome drug resistance. The main reason for the resistance of small molecule inhibitor of EGFR is the occurrence of point mutation, which makes the inhibitor lose the inhibitory effect on the target protein, while PROTAC targeting EGFR technology can degrade the target protein and overcome the resistance caused by point mutation.

Application

EGFR PROTAC is still mainly used in the preclinical research stage for anti-tumor effect research. For example, PROTAC-C1 /3/4 are three kinds of EGFR PROTAC products. Preclinical studies have shown that C1 can penetrate the membrane of human nest cancer cell OVCAR 8 and induce EGFR protein degradation at low nanomolar concentrations. C3 can degrade the EGFR protein with L858R activation point mutation caused by exon 19 deletion in human lung cancer cell H3255. C4 can degrade the gefitinib resistant double mutant (L858R/T790M) type EGFR protein in non-small cell lung adenocarcinoma H1975 cells. In addition, a potent and highly selective PROTAC targeting EGFR-L858R mutants, CFT8919, has been disclosed to be in IND-enabling preclinical studies for the treatment of non-small-cell lung cancer.

Our Services

• Selection of EGFR ligands
• Screening of PROTAC linkers
• Design and synthesis of EGFR PROTACs
• Evaluation of EGFR PROTACs in vitro / in vivo

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* PROTAC^® is a registered trademark of Arvinas Operations, Inc., and is used under license.