Spirocyclic dimer SpiD7 activates the unfolded protein response to selectively inhibit growth and induce apoptosis of cancer cells

• DOI: 10.1016/j.jbc.2022.101890
• Publication Date: 2022-04-01T06:04:27Z
• Authors: Smit Kour; Sandeep Rana; Sydney P. Kubica; Smitha Kizhake; Mudassier Ahmad; Catalina Muñoz-Tr...; David Klinkebiel; Sarbjit Singh; Jayapal Reddy Mal...; Surabhi Chandra; Nicholas T. Woods; Adam R. Karpf; Amarnath Natarajan
• Keywords: 0303 health sciences; Accelerated Communication; Carcinoma; Eukaryotic Initiation Factor-2; Apoptosis; Endoplasmic Reticulum; Endoplasmic Reticulum Stress; 3. Good health; 03 medical and health sciences; Cell Line, Tumor; Drug Discovery; Unfolded Protein Response; Humans

The unfolded protein response (UPR) is an adaptation mechanism activated to resolve transient accumulation of unfolded/misfolded proteins in the endoplasmic reticulum. Failure such results UPR-mediated programmed cell death. Loss tumor suppressor gene or oncogene addiction cancer cells can result sustained higher basal UPR levels; however, it not clear if these levels be exploited as a therapeutic strategy. We hypothesized that covalent modification surface-exposed cysteine (SEC) residues could simulate activate UPR, and would provide necessary window. To test this hypothesis, here we synthesized analogs covalently modify multiple SEC evaluated them activators. identified spirocyclic dimer, SpiD7, its effects on activation signals, is, XBP1 splicing, phosphorylation eIF2α, decrease ATF 6 levels, normal cells, which were further confirmed by RNA-Seq analyses. found SpiD7 selectively induced caspase-mediated apoptosis whereas exhibited robust indicating stress. Furthermore, inhibited growth high-grade serous carcinoma lines ~3-15-fold more potently than immortalized fallopian tube epithelial (paired control) reduced clonogenic lines. Our suggest induction represents vulnerability discover novel therapeutics.