A Novel Squaramide Derivative, HR-19011, Induces the Integrated Stress Response via the HRI–eIF2α–ATF4 Pathway, Effectively Inhibiting Hematologic Malignancies
Bibliographic record
Abstract
We investigated the therapeutic potential and mechanisms of HR-19011, a novel eukaryotic translation initiation factor 2 subunit α (eIF2α) phosphorylation inducer, with a focus on its effects on the integrated stress response (ISR) pathway and cell-cycle regulation in K562 cells. Our findings revealed that HR-19011 exerts its anticancer effects primarily through the activation of heme-regulated inhibitor (HRI), leading to the phosphorylation of eIF2α, the induction of ISR signaling, and subsequent G1/S cell-cycle arrest. RNA sequencing analysis further highlighted significant changes in gene expression associated with the ISR pathway, particularly those involving the key components, activating transcription factor 4 and CHOP, underscoring the specific targeting of HRI by HR-19011. Additionally, HR-19011 suppressed the mTORC1 pathway, a critical regulator of cell growth and metabolism, through the downregulation of components such as phosphorylated S6K and phosphorylated 4EBP1, mediated by activating transcription factor 4 and CHOP. In vivo studies demonstrated that HR-19011 effectively inhibited tumor growth in a K562 xenograft model, without significant toxicity, and its broad efficacy across various hematologic malignancies further suggests its potential as a versatile anticancer agent. Our findings position HR-19011 as a promising candidate for targeting the HRI-eIF2α axis in cancer treatment, warranting further investigation and optimization for clinical application.
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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 | 0.001 | 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".