N-Phenyl ureidobenzenesulfonates, a novel class of human dihydroorotate dehydrogenase inhibitors inducing differentiation and apoptosis in acute myeloid leukemia cells
Bibliographic record
Abstract
N -Phenyl ureidobenzensulfonates (PUB-SOs) are a novel family of dihydroorotate dehydrogenase (DHODH) inhibitors. Herein, we investigate the potential of PUB-SOs to induce acute myeloid leukemia (AML) cell differentiation and apoptosis. To that end, we screened our chemolibrary to select the most potent PUB-SOs based on their antiproliferative activity and their ability to arrest the cell progression of AML cells in the S phase. The most promising PUB-SOs show antiproliferative activity in the range of 0.13–23 µM against THP-1, MOLM-13 and HL-60 AML cells. Moreover, those PUB-SOs arrested the cell cycle progression in the S phase. In addition, molecular docking studies evidenced their potential to bind in the brequinar-binding site located on DHODH which was confirmed using the DHODH inhibition assay showing that PUB-SOs are potent DHODH inhibitors (half maximal inhibitory concentration (IC 50 ) = 7.7–1000 nM). Our results also show that selected PUB-SOs induced the differentiation of THP-1 and HL-60 cells into cluster of differentiation (CD) 11b + /CD14 + phenotypes, up to 74 % and 50 %, respectively. They also promoted CD11b + differentiation in MOLM-13 cells (up to 44 %). Additionally, the prototypical PUB-SOs SFOM-0046 induced lactate dehydrogenase (LDH) release, mitochondrial stress and mitochondrial membrane potential loss in MOLM-13 cell line. Furthermore, SFOM-0046 induced apoptosis in MOLM-13 cells, which was confirmed by the increase of annexin V/propidium iodide (PI) and caspase 3/7 positive cells. In summary, our results highlight PUB-SOs as a novel family of DHODH inhibitors inducing both cell differentiation and apoptosis in AML cells, underscoring their potential as therapeutic agents for AML treatment. • PUB-SOs show IC 50 in the submicromolar to low micromolar range in AML cells. • MOLM-13 cells exhibit higher sensitivity to PUB-SOs than other AML cell lines. • PUB-SOs arrest the cell cycle in the S phase and induce apoptosis in AML cells. • They induce differentiation phenotypes (CD11b + /CD14 + ) in THP-1 and HL-60 cells. • They induce differentiation of MOLM-13 cells into CD11b + phenotype.
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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 | 0.000 | 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) | 0.000 | 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".