Targeting the Epidermal Growth Factor Receptor with Molecular Degraders: State-of-the-Art and Future Opportunities

Abstract

Epidermal growth factor receptor (EGFR) is an oncogenic drug target and plays a critical role in several cellular functions including cancer cell growth, survival, proliferation, differentiation, and motility. Several small-molecule tyrosine kinase inhibitors (TKIs) and monoclonal antibodies (mAbs) have been approved for targeting intracellular and extracellular domains of EGFR, respectively. However, cancer heterogeneity, mutations in the catalytic domain of EGFR, and persistent drug resistance limited their use. Different novel modalities are gaining a position in the limelight of anti-EGFR therapeutics to overcome such limitations. The current perspective reflects upon newer modalities, importantly the molecular degraders such as PROTACs, LYTACs, AUTECs, and ATTECs, etc., beginning with a snapshot of traditional and existing anti-EGFR therapies including small molecule inhibitors, mAbs, and antibody drug conjugates (ADCs). Further, a special emphasis has been made on the design, synthesis, successful applications, state-of-the-art, and emerging future opportunities of each discussed modality.

A partial epithelial‐mesenchymal transition signature for highly aggressive colorectal cancer cells that survive under nutrient restriction

“…Since EGFR is a key regulator of cell proliferation [44], we aimed to further investigate its role in starvation‐induced p‐EMT. First, we examined by western blotting the protein levels of two target genes of the EGFR signalling cascade, total Cyclin D1 and c‐Myc.…”

Discovery of Potent SOS1 PROTACs with Effective Antitumor Activities against NCI-H358 Tumor Cells In Vitro/In Vivo

“…PROTAC, degrading the entire protein to eliminate both enzymatic activity and nonenzymatic kinase functions, has a unique advantage over traditional small-molecule drugs against resistance. − Till now, a few of SOS1 degraders have been disclosed, such as degrader S4 , S5 , and S6 (Figure ). The degrader S4 achieved up to 92% SOS1 degradation in both CRC cell lines and PDOs and could inhibit KRAS G12A CRC organoid viability with a moderate IC 50 of 480 nM .…”

Design, Synthesis, and Biological Evaluation of Novel EGFR PROTACs Targeting C797S Mutation

“…15,16 Given the advantages of PROTAC, many PROTACs targeting EGFR have been developed. 17,18 However, most EGFR PROTACs are designed based on first-, second-, and thirdgeneration small inhibitors, which selectively degrade EGFR Del19 , EGFR L858R , or EGFR L858R/T790M , but lack effective degradation activity against the C797S mutant (Figure 1). 19−27 Currently, a few PROTACs targeting the C797S mutation have been reported and they are generally designed based on the allosteric inhibitor EAI001 and the orthosteric inhibitor Brigatinib (Figure 2).…”

“…The significant feature of this strategy is that it can effectively degrade target proteins through catalytic amounts of drugs to achieve therapeutic functions . Compared with traditional small-molecule inhibitors, PROTAC has the advantages of overcoming drug resistance, targeting undruggable proteins, and high target selectivity. , Given the advantages of PROTAC, many PROTACs targeting EGFR have been developed. , However, most EGFR PROTACs are designed based on first-, second-, and third-generation small inhibitors, which selectively degrade EGFR Del19 , EGFR L858R , or EGFR L858R/T790M , but lack effective degradation activity against the C797S mutant (Figure ). − Currently, a few PROTACs targeting the C797S mutation have been reported and they are generally designed based on the allosteric inhibitor EAI001 and the orthosteric inhibitor Brigatinib (Figure ).…”

“…The experimental animal and protocol were carried out according to IACUC of China Pharmaceutical University. The animals used for pharmacokinetic study were 10 male SPF SD rats (6−8 weeks, 200−230 g), and the animals used for the efficacy study were 18 ■ ABBREVIATIONS…”