![[feed]](/style/images/feed-icon-14x14.png){kind=icon}
|
PDF (Original Paper)
- Requires a PDF viewer such as GSview, Xpdf or Adobe Acrobat Reader
11MB | |
![[img]](http://edoc.mdc-berlin.de/style/images/fileicons/other.png) |
Other (Supplementary Material)
6MB |
| Item Type: | Article |
|---|---|
| Title: | Discovery of tetrazolo-pyridazine-based small molecules as inhibitors of MACC1-driven cancer metastasis |
| Creators Name: | Yan, S. and Schöpe, P.C. and Lewis, J. and Putzker, K. and Uhrig, U. and Specker, E. and von Kries, J.P. and Lindemann, P. and Omran, A. and Sanchez-Ibarra, H.E. and Unger, A. and Zischinsky, M.L. and Klebl, B. and Walther, W. and Nazaré, M. and Kobelt, D. and Stein, U. |
| Abstract: | Metastasis is directly linked to poor prognosis of cancer patients and warrants search for effective anti-metastatic drugs. MACC1 is a causal key molecule for metastasis. High MACC1 expression is prognostic for metastasis and poor survival. Here, we developed novel small molecule inhibitors targeting MACC1 expression to impede metastasis formation. We performed a human MACC1 promoter-driven luciferase reporter-based high-throughput screen (HTS; 118.500 compound library) to identify MACC1 transcriptional inhibitors. HTS revealed 1,2,3,4-tetrazolo[1,5-b]pyridazine-based compounds as efficient transcriptional inhibitors of MACC1 expression, able to decrease MACC1-induced cancer cell motility in vitro. Structure-activity relationships identified the essential inhibitory core structure. Best candidates were evaluated for metastasis inhibition in xenografted mouse models demonstrating metastasis restriction. ADMET showed high drug-likeness of these new candidates for cancer therapy. The NFκB pathway was identified as one mode of action targeted by these compounds. Taken together, 1,2,3,4-tetrazolo[1,5-b]pyridazine-based compounds are effective MACC1 inhibitors and pose promising candidates for anti-metastatic therapies particularly for patients with MACC1-overexpressing cancers, that are at high risk to develop metastases. Although further preclinical and clinical development is necessary, these compounds represent important building blocks for an individualized anti-metastatic therapy for solid cancers. |
| Keywords: | High-Throughput Screening, Cancer Metastasis, MACC1, Transcriptional Inhibitors, Tetrazolo-Pyridazine, Animals, Mice |
| Source: | Biomedicine & Pharmacotherapy |
| ISSN: | 0753-3322 |
| Publisher: | Elsevier |
| Volume: | 168 |
| Page Range: | 115698 |
| Date: | December 2023 |
| Official Publication: | https://doi.org/10.1016/j.biopha.2023.115698 |
| PubMed: | View item in PubMed |
Repository Staff Only: item control page
Download Statistics
Download Statistics
