Degrading mutant IDH1 employing a PROTAC-based approach impairs STAT3 activation.

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Tác giả: Hashnu Dutta, Nishant Jain

Ngôn ngữ: eng

Ký hiệu phân loại: 976.402 Spanish and French periods, 1680-1821

Thông tin xuất bản: United States : Archives of biochemistry and biophysics , 2025

Mô tả vật lý:

Bộ sưu tập: NCBI

ID: 90490

Heterozygous mutations in IDH1 (isocitrate dehydrogenase 1) are found in most grade II and III brain tumors. A slew of mutant IDH1 inhibitors were identified soon after the discovery of IDH1 mutations in brain tumors. But recent reports show that mutant IDH1 inhibitors reverse therapeutic vulnerabilities and activate the oncogenic transcription factor STAT3 in mutant IDH1-expressing cells. Thus, inhibiting mutant IDH1 using mutant IDH1-specific inhibitors can result in drug resistance. Therefore, to block mutant IDH1, it is imperative to identify alternative modes of therapy. In these lines, recent findings show that PROteolysis TArgeting Chimera (PROTAC) molecules can be designed to degrade target proteins in cancer cells. However, it is unknown whether degrading mutant IDH1 leads to STAT3 activation. Therefore, in this study, we asked if degrading mutant IDH1 by employing a PROTAC-based approach leads to STAT3 activation. To answer the question, we adopted the dTAG system, where we fused FKBP12
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