In this paper, we designed and synthesized a series of small molecule PROTACs targeting EGFR utilizing WZ4002, known for its mutation selectivity, as the warhead...Further analysis through protein immunoblotting revealed that HJM- 17 effectively reduced the expression of EGFRL858R/T790M. These active compounds lay the groundwork for future studies focused on EGFR-targeting PROTACs.

P1, N=93, Recruiting, BeiGene | Not yet recruiting --> Recruiting

Notably, CDDO-Me attenuates TNBC progression by accelerating EGFR degradation in cell-derived xenografts and patient-derived organoid models, highlighting its clinical application potential. Consequently, induction of EGFR degradation through MG degraders represents a viable therapeutic strategy for TNBC.

P1, N=93, Not yet recruiting, BeiGene

Osimertinib has become the first globally accessible third-generation EGFR inhibitor, representing one of the most advanced developments in non-small-cell lung cancer (NSCLC) therapy...These degraders compared with EGFR inhibitors showed better efficiency in their cellular potency, inhibition, and toxicity profiles. In this review, we first introduce the structural properties of EGFR, the resistance, and mutations of EGFR, and then mainly focus on the recent advances of EGFR-targeting degraders along with its advantages and outstanding challenges.

Compound 12c also exhibited promising inhibitory activity, as well as degradation efficiency in vivo. Our study highlights that EGFR-ATTECs could be developed as a new expandable EGFR degradation tool and also reveals a novel potential therapeutic strategy to prevent drug resistance acquired EGFR mutations.

Our results reveal the interaction mechanisms through which GMI induces EGFR degradation and abolishes EGFR-mediated intracellular pathway. Our study indicates that GMI is an EGFR degrader for inhibiting EGFR-expressing tumor growth.

We discovered that ERBB2+ cancer cells are enriched with poly U sequences on their 3'UTR which are mRNA-stabilizing sequences. We developed a novel technology, in which we engineered these ERBB2 mRNA-stabilizing sequences to unstable forms that successfully overwrote and outcompeted the endogenous ERBB2 mRNA-encoded message and degraded ERBB2 transcripts which led to the loss of the protein across multiple cancer cell types both in the wildtype and drug-resistance settings in vitro and in vivo, offering a unique safe novel modality to control ERBB2 mRNA and other pervasive oncogenic signals where current targeted therapies fail.

These findings reveal the emerging character of CMTM7 in Wnt/β-catenin signaling and bring new sights of gene interaction. CMTM7 and other elements in the feedback loop may serve as emerging targets for breast cancer therapy.

These results indicate that calcineurin stabilizes EGFR by dephosphorylating S1046/1047 and promotes tumor growth. These findings suggest that calcineurin may be a new therapeutic target for cancers with high EGFR expression or activation.

Proteasomal USP14 and UCHL5 act collectively to promote cell surface recovery of EGFR. Inhibition of proteasomal deubiquitylase activity induces increased EGFR ubiquitylation and retention on recycling endosomes. The USP14 and UCHL5 dual inhibitor b-AP15 elicits potent tumor-suppressive effects to deter cell proliferation and induce apoptotic cell death in lung cancer.