Abstract 1169: Characterization of a small molecule inhibitor for GD3 synthase (ST8SIA1), a novel target in breast cancer stem-like cells
Bibliographic record
Abstract
Abstract We reported that GD2 selectively identifies breast cancer stem-like cells (BCSCs) in TNBCs and that the enzyme ST8SIA1 regulates GD2 biosynthesis. We have shown that knockout of ST8SIA1 expression in TNBC cell lines inhibits tumor growth and metastasis in vivo, whereas ST8SIA1 overexpression induces epithelial-to-mesenchymal transition, leading to metastasis of TNBC cells. Very recently we have shown that ST8SIA1 regulates focal adhesion kinase (FAK)/AKT/mammalian target of rapamycin (mTOR) signaling in GD2+ BCSCs. Here we hypothesize that inhibition of ST8SIA1 activity using small molecule inhibitors targets BCSC function. Because of a lack of a crystal structure for developing small-molecule inhibitors of ST8SIA1, we developed a homolog of ST8SIA1 using the crystal structure of ST8SIA3 (PDB ID: 5B09) as a template. ST8SIA3 shares 32% identity and 54% similarity with this crystal structure. To this model we docked GM3, the substrate for the ST8SIA1 enzyme and analyzed their interactions. Next, we used this model to dock the compound library to identify potential inhibitors of ST8SIA1. To that end, we performed structure-based virtual screening or virtual ligand screening of 10,000 compounds based on the structure of GM3 (>70% identity), which we retrieved from the ChemSpider database. Similarly, we retrieved 1500 compounds based on the parent structure of flavone (>70% identity) from the ZINC database. After further filtration and selection of these structures, we ranked these compounds on the basis of 11 different scoring functions in DS 4.5. We selected the top candidate (ZINC02886919) for further functional characterization. ZINC02886919 had a predicted binding affinity (-logKd) of 6.17, with which we calculated the predicted Kd as 0.812 μM. Visualization analysis demonstrated that ZINC02886919 is involved in both polar and hydrophobic interactions in the binding pocket. We then synthesized ZINC02886919 and pursued pharmacological and in vitro assays. Treatment of SUM159 cells with ZINC02886919 decreased the percentage of GD2+ BCSCs by 5- to 10-fold within 72h in a concentration-dependent manner (from 31% to 6%). In addition, ZINC02886919 inhibited soft agar colony and mammosphere formation for SUM159 cells by 10- to 20-fold. These data indicated that the ST8SIA1 homolog model that we developed shares structural similarity with native human ST8SIA1 protein and that ZINC02886919 is a potential inhibitor of ST8SIA1 activity and thus BCSC function. In conclusion, inhibition of ST8SIA1 expression or activity inhibits BCSC function, TNBC tumor growth, and metastasis. The ST8SIA1 inhibitor ZINC02886919 inhibits GD2 expression and mammosphere and soft agar colony formation in vitro. The effect of ZINC02886919 on tumor growth and metastasis is currently being tested in vivo. Citation Format: Appalaraju Jappupilli, Khoa Nguyen, Stanley Ly, Michael Andreeff, Prashen Chelikani, Venkata Lokesh Battula. Characterization of a small molecule inhibitor for GD3 synthase (ST8SIA1), a novel target in breast cancer stem-like cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1169.
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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".