Abstract 807: Selamectin and ivermectin are small molecule inhibitors that interfere with Sin3A-PAH2 function and exert anti-tumor activity in triple-negative breast cancer
Bibliographic record
Abstract
Abstract INTRODUCTION: Sin3 is a complex scaffolding protein that participates in epigenetic regulation involved in a variety of biological processes, including chromatin remodeling, development, differentiation, cell cycle and survival. Paired Amphipathic domain 2 (PAH2) domain of Sin3 was shown to interact with Sin3 interacting domain (SID)-containing transcription factors, such as Mxd1, KLF10/11, and REST. Previously, we reported that SID transcripts and decoy peptides disrupt the interactions between Sin3-PAH2 domain and SID-containing transcription factors and induce epigenetic reprogramming in TNBC. RESULTS AND CONCLUSION: Here we show that fourteen SMIs mimicking SID decoys were identified by in silico computation from a chemical library composed of 115,000 compounds. We confirmed that selamectin and ivermectin are SID decoys using duo-link assays. Our NMR 15N-HSQC spectroscopy binding results further demonstrated ivermectin, which shares the same binding site as selamectin, directly interacted with PAH2. Moreover, selamectin inhibited Sin3 repression activity as measured by mammalian two-hybrid and in vitro GST pull-down assays. Notably, ivermectin was approved by Food and Drug Administration (FDA) to treat small animals and human. However, the anti-tumorigenic roles for these SMIs had not been investigated in TNBC in vitro and in vivo. Remarkably, these SMIs did not affect growth in 2-dimensional (2D) clonogenecity assay, but significantly suppressed growth in 3D matrigel and tumorsphere cultures. Moreover, selamectin significantly suppressed Myc mammary tumor growth in vivo more than 50 percent without any cytotoxicity. Selamectin and ivermectin induced re-expression of CDH1 and ESR1, restoring tamoxifen sensitivity. Treatment with these compounds inhibited in vitro invasion as measured by Boyden chamber in MCF7/ADR and MDA-MB-231 cells. Selamectin and ivermectin were shown to alleviate multidrug resistance and enhance doxorubicin and paclitaxel cytotoxicity in MCF7/ADR cells, which is unrelated to disruption of Sin3-PAH2. Based on further studies of the Sin3A complexes using selamectin and ivermectin, we seek to identify novel SMIs with better efficiency for targeting Sin3 complex and treating TNBCs in the future. Citation Format: Yeon-Jin Kwon, Boris A. Leibovitch, Lei Zeng, Mihaly Mezei, Rossitza Christova, Shuai Yang, Rajal Sharma, Edgardo Aritzia, nidhi bansal, Ming-Ming Zhou, Authur Zelent, Eduardo Farias, Samuel Waxman. Selamectin and ivermectin are small molecule inhibitors that interfere with Sin3A-PAH2 function and exert anti-tumor activity in triple-negative breast cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 807. doi:10.1158/1538-7445.AM2014-807
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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 | 0.000 |
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 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".