Abstract LB-A13: Cellular characterization of the selective inhibition of UBA5 by organometallic, adenosine-based inhibitors
Bibliographic record
Abstract
Abstract Cells that undergo higher protein turnover, such as pancreatic secretory cells and cancerous cells, have the propensity to undergo endoplasmic reticulum (ER) stress. If left uncorrected, ER stress can result in the initiation of apoptosis. To avoid these fates, cells have developed support systems to counteract the apoptotic effects of ER stress, such as conjugation of certain stress-associated proteins with the ubiquitin-fold modifier 1 (UFM1) ubiquitin-like protein. Our research has recently focused on the discovery and in vitro validation of the first selective inhibitor of the UFM1 pathway, 5C-Z, which selectively targets the UFM1 E1 enzyme (UBA5) over other related enzymes and a panel of over 90 human kinases. This novel strategy of inhibiting UBA5 and subsequent UFMylation would make cancer cells that are highly dependent on this system more susceptible to pharmacological disturbances in ER homeostasis, which could lead to the use of milder drug dosing strategies. Our current efforts are focused on studying the effects of 5C-Z on intracellular signalling, the cellular distribution of proteins in the UFM1 pathway, and phenotypic changes within a lung cancer cell lung line (Sk-Luci6). Treatment of lung cancer cells that exhibit high levels of UBA5 protein expression results in decreased cell proliferation (EC50 = 216.9 μM, 95% C.I. = 211.5 - 222.5 μM), yet does not induce cell death in other diseased (A549) or healthy (MRC9) lung cells (up to 200 μM). The decreased cellular proliferation upon 5C-Z treatment mirrors the effect of treatment with UBA5 siRNA. Using immunocytochemistry, it appears that treatment with 5C-Z also induces changes in both cellular morphology and the distribution of UBA5-like staining within the cell. Furthermore, there is an apparent decrease in UFM1-like co-localization with its E2 conjugating enzyme (UFC1) after prolonged incubation with 5C-Z, although further intracellular analysis is required to confirm this observation. Preliminary work also indicates that these cellular effects may also be selective against the UFM1 pathway compared to related ubiquitin-like labelling pathways. We are currently evaluating the effects of 5C-Z on ER stress signalling pathways connected to the UFM1 labelling system. Citation Format: Sara R. da Silva, Mulu Geletu, Fiza Javed, Stacey-Lynn Paiva, Andrew M. Lewis, Honglin Li, Patrick T. Gunning. Cellular characterization of the selective inhibition of UBA5 by organometallic, adenosine-based inhibitors. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr LB-A13.
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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) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 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 | 0.000 |
| Insufficient payload (model declined to judge) | 0.002 | 0.001 |
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".