Abstract 2510: A porphodimethene chemical inhibitor of uroporphyrinogen decarboxylase
Bibliographic record
Abstract
Abstract Uroporphyrinogen decarboxylase (UROD), a heme biosynthetic pathway enzyme that converts uroporphyrinogen to coproporphyrinogen, was recently identified as a potential anticancer target. UROD inhibition leads to an increase in reactive oxygen species (ROS), likely mediated by the Fenton reaction, which decreases cancer cell viability and sensitizes cells to cisplatin and radiation. Because there is no known chemical UROD inhibitor suitable for translational research, we aimed to design, synthesize, and characterize such a compound. In silico design and docking was used to identify a potential porphyrin analogue. Subsequent synthesis produced a porphodimethene (named PI-16) that inhibited UROD in an enzymatic assay (IC50 = 9.9 µM). PI-16 did not affect porphobilinogen deaminase (at 62.5 µM), thereby exhibiting some specificity. In cellular assays, PI-16 reduced FaDu and ME-180 cancer cell viability with half maximal effective concentrations of 22.7 µM and 26.9 µM, respectively, whereas normal oral epithelial (NOE) cells were only minimally affected. PI-16 combined effectively with cisplatin and radiation, with potent synergy being observed with cisplatin (Chou-Talalay combination index < 1). This work presents the first known synthetic UROD inhibitor, and sets the foundation for the design, synthesis, and characterization of higher affinity and more effective compounds. Citation Format: Kenneth W. Yip, Zhan Zhang, Noriko Sakemura-Nakatsugawa, Jui-Wen Huang, Shijun Yue, Yulia Jitkova, Terence To, Emil Pai, Aaron Schimmer, Jonathan Lovell, Jonathan Sessler, Fei-Fei Liu. A porphodimethene chemical inhibitor of uroporphyrinogen decarboxylase. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2510. doi:10.1158/1538-7445.AM2014-2510
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 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) | 0.000 | 0.000 |
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 teacher head, 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".