Abstract LB-354: A novel orally-bioavailable small-molecule inhibitor of Stat3 regresses human breast and lung cancer xenografts
Bibliographic record
Abstract
Abstract Constitutive activation of STAT3, a member of the Signal Transducer and Activator of Transcription (STAT) family of proteins, occurs with a high frequency in diverse human tumors and is a molecular abnormality promoting carcinogenesis and tumor progression. Although STAT3 has been targeted for anticancer drug development, there is presently no STAT3 drug in the clinic. To identify potent therapeutics for tumors harboring constitutively-active STAT3, the key dimerization step in STAT3 activation was targeted in small-molecule drug development. A novel, orally bio-available small-molecule inhibitor has been identified that binds STAT3 SH2 domain with a KD of 504 nM. BP-1-102 blocks constitutively-active STAT3 signaling and selectively inhibits growth, survival, migration and invasion of diverse STAT3-dependent tumor cells in vitro. BP-1-102-mediated inhibition of aberrantly-active STAT3 in tumor cells suppresses the expression of c-Myc, Cyclin D1, Bcl-xL, Survivin, and vascular endothelial growth factor (VEGF). Further, treatment with BP-1-102 of breast cancer cells harboring aberrantly-active STAT3 disrupts STAT3-NFκB cross-talk and blocks the phosphorylation of focal adhesion kinase and paxillin, while enhancing E-cadherin expression. Intravenous or oral administration of BP-1-102 furnishes micromolar or microgram levels in tumor tissues and inhibits growth of human breast and lung tumor xenografts. Data together identify BP-1-102 as a small-molecule STAT3 inhibitor with a great potential for clinical development. The oral bioavailability represents a substantial advancement in the discovery of small-molecule STAT3 inhibitors as novel anticancer drugs. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-354. doi:1538-7445.AM2012-LB-354
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
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 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 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".