Abstract 4512: A novel orally-bioavailable salicylic acid-based small molecular Stat3 inhibitor suppress growth of human breast tumor xenografts
Bibliographic record
Abstract
Abstract With the critical role of aberrantly active Signal Transducer and Activator of Transcription (Stat) 3 protein in many human cancers, selective small molecular inhibitors targeting the dimerization event would be valuable as therapeutic agents and as chemical probes to clarify the complex biological functions of Stat3. By computational and structural analyses of the interaction between Stat3 and the lead dimerization disruptor, S3I-201.1066, we have designed a diverse set of analogs. We present evidence from in vitro studies that BP-1-102, a structural analog of S3I-201.1066, directly interacts with Stat3, with an affinity (KD) of 504 nM, inhibits in vitro Stat3 DNA-binding activity, with IC50 of 6.8 μM, and selectively inhibits Stat3 activity in human and mouse tumor cell lines that harbor constitutively-active Stat3. By contrast, BP-1-102 has little or no effect on pShc, pJak, pSrc, and pErk levels. Furthermore, BP-1-102 significantly and specifically suppressed the viability, proliferation, and survival of same malignant cell lines harboring aberrant Stat3 at low concentration, with little or no effect on normal NIH3T3 mouse fibroblasts or the mouse thymus epithelial stromal cells (TE-71) that do not harbor aberrant Stat3 activity. Furthermore, treatment of malignant cells harboring aberrant Stat3 activity with BP-1-102 down-regulated the expression of c-Myc, Cyclin D1, Bcl-xL, Survivin, and VEGF, which are known Stat3-regulated genes. These results together strongly suggest the anti-tumor cell effects of BP-1-102 is largely dependent on the inhibition of aberrant Stat3 activity. Significantly, BP-1-102 induced strong antitumor response in mouse xenografts of human breast cancer when administered via intravenous or oral gavage. Our studies identify a novel small-molecule that binds with a high affinity to Stat3 and that blocks Stat3 activation and function, and thereby induces antitumor response in human breast tumor xenografts harboring aberrant Stat3. Key Words: Stat3 inhibitor, antitumor, xenograft, BP-1-102, S3I-201.1066 Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4512. doi:10.1158/1538-7445.AM2011-4512
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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".