Abstract 4989: Selective inhibitors of the inositol-requiring enzyme 1 kinase domain
Bibliographic record
Abstract
Abstract Inositol-requiring enzyme 1 (IRE1) is a key player in endoplasmic reticulum (ER) stress conditions. IRE1 is a highly conserved ER-membrane protein activated by the unfolded protein response (UPR) or other ER-stressors, such as hypoxia and glucose deprivation. Stress causes IRE1 to undergo oligomerization and autophosphorylation, which triggers nonconventional splicing of XBP-1 mRNA by its cytosolic endonuclease domain. The resulting spliced XBP-1 protein (XBP-1s) is a transcription factor that serves to increase the protein folding capacity and ultimately restore homeostasis of the ER. Thus, sustained IRE1 activity promotes cell survival and inhibition of IRE1 may be a potential therapeutic target for diseases associated with chronic ER-stress, such as neurodegenerative disorders, diabetes, and cancer. Proper RNase function of IRE1 is dependent upon autophosphorylation of the kinase domain. We therefore screened a library of 380 known kinase inhibitors, consisting of tool compounds and compounds already in clinical use, for those with activity against the human IRE1 kinase domain. As a result, a number of compounds were found that potently inhibit phosphorylation of a biotin-STK peptide substrate in the presence of human IRE1 (IC50 < 1 μM), as determined by HTRF (homogeneous time-resolved fluorescence). The lead compounds were then screened in cell-based assays. Several ATP-mimetic compounds with diverse chemotypes were found to inhibit expression of XBP-1s in human cancer cells under pharmacologically-induced acute ER-stress. Furthermore, transcriptional targets of XBP-1s and phosphorylation of IRE1 were also negatively affected by these compounds. Interestingly one compound in particular, a known ROCK1 (Rho-associated coiled-coil containing protein kinase 1) inhibitor (OICR000287A), was significantly more toxic to cells under acute ER-stress than to unstressed cells. This study suggests that development of ATP-competitive inhibitors of human IRE1 is a promising therapeutic strategy for ER-stress related diseases including myeloma, pancreatic and other secretory cancers. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4989. doi:1538-7445.AM2012-4989
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.004 | 0.002 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".