Abstract 2530: The anticancer kinase inhibitor dovitinib (TKI258/CHIR258) may have multiple modes of action because it also binds DNA and inhibits topoisomerase I and topoisomerase IIα
Bibliographic record
Abstract
Abstract Dovitinib (TKI258/CHIR258) is a kinase inhibitor in phase II development for the treatment of renal cell carcinoma, advanced breast cancer, and relapsed multiple myeloma. Dovitinib is thought to exert anticancer effects through its binding to and kinase inhibition of fibroblast growth factor receptor 3 (FGFR3). It also strongly inhibits a number of other kinases that are members of the RTK superfamily, including the vascular endothelial growth factor receptor (VEGFR); fibroblast growth factor receptor 1 (FGFR1); platelet-derived growth factor receptor type 3; FMS-like tyrosine kinase 3 (FLT3); stem cell factor receptor (c-KIT) and colony-stimulating factor receptor 1 (CSF1R) all of which may also contribute to its anticancer activity. In terms of its chemical structure dovitinib is a benzimidazole-quinolinone compound. Thus, structurally it resembles the bisbenzimidazole minor groove binding dye Hoechst 33258. Molecular modeling studies of the docking of dovitinib into an X-ray structure of a Hoechst 33258-DNA complex showed that dovitinib could be reasonably accommodated in the minor groove. Dovitinib was shown to bind to DNA by its ability to increase the DNA melting temperature. Changes in the visible absorbance and fluorescence spectrum of dovitinib that occurred upon addition of DNA were also consistent with DNA binding. Because DNA binders are often topoisomerase I and topoisomerase II inhibitors, the ability of dovitinib to inhibit these DNA processing enzymes was also investigated. Dovitinib inhibited both the decatenation activity and the ATPase activity of topoisomerase IIα in the low micromolar concentration range. Dovitinib was also able to stabilize the topoisomerase IIα-cleavage complex and act as a topoisomerase IIα poison with activity comparable to etoposide as measured by its ability to induce formation of linear DNA. Dovitinib was also examined for its ability to increase phosphorylation of H2AX in K562 cells to determine if it could act as a cellular topoisomerase II poison and induce double strand DNA breaks. Dovitinib was also able to inhibit the topoisomerase I-catalyzed relaxation of DNA. In conclusion, the anticancer activity of dovitinib may result not only from its ability to inhibit multiple kinases, but also from its ability to target topoisomerase I and topoisomerase IIα. Support: CIHR and a Canada Research Chair in Drug Development to BBH and an NIH grant (CA090787) to JCY. 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 2530. doi:10.1158/1538-7445.AM2011-2530
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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 | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.020 | 0.004 |
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".