Small molecule STAT3/5 inhibitors exhibit therapeutic potential in acute myeloid leukemia and extra-nodal natural killer/T cell lymphoma
Bibliographic record
Abstract
Abstract Background: The oncogenic transcription factors STAT3, STAT5A and STAT5B are essential to steer hematopoiesis and immunity, but their enhanced expression and activation drives the development or progression of blood cancers, such as AML and NKCL. Current therapeutic strategies to inhibit STAT3/5 activity focus on blocking upstream tyrosine kinases, but frequently occurring resistance often leads to disease relapse, emphasizing the need for new STAT3/5 targeted therapies. Methods: Cytotoxicity assays were used to assess the impact of our STAT3/5 inhibitors JPX-0700/JPX-0750 on cell viability alone, or in combination with approved antineoplastic agents, in NKCL or AML cancer cell lines and primary AML patient samples. To identify genetic abnormalities of cell lines, we utilized array comparative genome hybridization. Western blotting and flow cytometry were employed to elucidate the mechanisms of the inhibitors on cell viability, cell cycle and STAT3/5 downstream signaling. In order to evaluate the effectiveness and safety of these compounds in vivo, we established AML and NKCL mouse xenografts and administered daily intraperitoneal injections of the inhibitors. Results: Our STAT3/5 degraders selectively reduced STAT3/5 activation and total protein levels, as well as downstream target oncogene expression, exhibiting nanomolar to low micromolar efficacy in inducing cell death in AML/NKCL cell lines and AML patient samples. We found that both AML/NKCL cells hijack STAT3/5 signaling through either upstream activating mutations in tyrosine kinases, activating gain-of-function mutations in STAT3, mutational loss of negative STAT regulators, or genetic gains in anti-apoptotic, pro-proliferative or epigenetic-modifying STAT3/5 targets, emphasizing STAT3/5 as valid targets in these diseases. JPX-0700/-0750 treatment reduced leukemic cell growth in human AML or NKCL xenograft mouse models, without adverse side effects. Additionally, we observed synergistic cell death induced by JPX-0700/-0750 upon combinatorial use with approved chemotherapeutics in AML/NKCL cell lines and AML patient blasts. Conclusion: We demonstrate the effectiveness of dual pharmacologic inhibition of phospho- and total STAT3/5 by JPX inhibitors in AML and NKCL, emphasizing their essential roles in initiating and driving these cancers. These potent small molecule degraders of STAT3/5 could propel further clinical development and may emerge as highly effective combinatorial partners for the treatment of AML and NKCL patients.
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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) | 0.004 | 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".