Discovery of a molecular glue for EGFR degradation

	Discovery of a molecular glue for EGFR degradation
	Wang, HR; Wang, H; Wang, R; Li, YZ; Wang, ZP; Zhou, WS; Deng, L; Li, XY; Zou, L; Yang, Q; Lai, R; Qi, XW; Nie, JY; Jiao, BW
	2024
发表期刊	ONCOGENE
ISSN	0950-9232
摘要	Aberrant expression of epidermal growth factor receptor (EGFR) plays a critical role in the pathogenesis of various tumors, potentially representing a target for therapeutic intervention. Nonetheless, EGFR remains a challenging protein to target pharmacologically in triple-negative breast cancer (TNBC). An emerging approach to address the removal of such proteins is the application of molecular glue (MG) degraders. These compounds facilitate protein-protein interactions between a target protein and an E3-ubiquitin ligase, subsequently leading to protein degradation. Herein, we identified a new MG (CDDO-Me, C-28 methyl ester of 2-cyano-3, 12-dioxooleana-1, 9(11)-dien-28-oic acid), which orchestrated binding between EGFR and KEAP1 (an E3-ubiquitin ligase adapter), thereby initiating the ubiquitination and degradation of EGFR. CDDO-Me directly interacted with the tyrosine kinase (TK) domain of EGFR, resulting in its degradation via an autophagy-dependent lysosomal pathway. Knockdown of KEAP1 decreased the degradation of EGFR by reducing its K63-linked ubiquitination, leading to diminished EGFR colocalization in autophagosomes and lysosomes. 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.
收录类别	SCI
语种	英语
文献类型	期刊论文
条目标识符	http://ir.kiz.ac.cn/handle/152453/14547
专题	科研部门_发育的印迹调控与进化学（焦保卫）
推荐引用方式 GB/T 7714	Wang, HR,Wang, H,Wang, R,et al. Discovery of a molecular glue for EGFR degradation[J]. ONCOGENE,2024.
APA	Wang, HR.,Wang, H.,Wang, R.,Li, YZ.,Wang, ZP.,...&Jiao, BW.(2024).Discovery of a molecular glue for EGFR degradation.ONCOGENE.
MLA	Wang, HR,et al."Discovery of a molecular glue for EGFR degradation".ONCOGENE (2024).

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