Discovery of Sulfonamidebenzamides as Selective Apoptotic CHOP Pathway Activators of the Unfolded Protein Response
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- 作者：Daniel P. Flaherty ; Justin R. Miller ; Danielle M. Garshott ; Michael Hedrick ; Palak Gosalia ; Yujie Li ; Monika Milewski ; Eliot Sugarman ; Stefan Vasile ; Sumeet Salaniwal ; Ying Su ; Layton H. Smith ; Thomas D. Y. Chung ; Anthony B. Pinkerton ; Jeffrey Aub茅 ; Michael U. Callaghan ; Jennifer E. Golden ; Andrew M. Fribley ; Randal J. Kaufman
- 刊名：ACS Medicinal Chemistry Letters
- 出版年：2014
- 出版时间：December 11, 2014
- 年：2014
- 卷：5
- 期：12
- 页码：1278-1283
- 全文大小：246K
- ISSN：1948-5875
文摘
Cellular proteins that fail to fold properly result in inactive or disfunctional proteins that can have toxic functions. The unfolded protein response (UPR) is a two-tiered cellular mechanism initiated by eukaryotic cells that have accumulated misfolded proteins within the endoplasmic reticulum (ER). An adaptive pathway facilitates the clearance of the undesired proteins; however, if overwhelmed, cells trigger apoptosis by upregulating transcription factors such as C/EBP-homologous protein (CHOP). A high throughput screen was performed directed at identifying compounds that selectively upregulate the apoptotic CHOP pathway while avoiding adaptive signaling cascades, resulting in a sulfonamidebenzamide chemotype that was optimized. These efforts produced a potent and selective CHOP inducer (AC50 = 0.8 渭M; XBP1 > 80 渭M), which was efficacious in both mouse embryonic fibroblast cells and a human oral squamous cell cancer cell line, and demonstrated antiproliferative effects for multiple cancer cell lines in the NCI-60 panel.