TY  - JOUR
AU  - Yan, Shixian
AU  - Schöpe, Paul Curtis
AU  - Lewis, Joe
AU  - Putzker, Kerstin
AU  - Uhrig, Ulrike
AU  - Specker, Edgar
AU  - von Kries, Jens Peter
AU  - Lindemann, Peter
AU  - Omran, Anahid
AU  - Sanchez-Ibarra, Hector E
AU  - Unger, Anke
AU  - Zischinsky, Mia-Lisa
AU  - Klebl, Bert
AU  - Walther, Wolfgang
AU  - Nazaré, Marc
AU  - Kobelt, Dennis
AU  - Stein, Ulrike
TI  - Discovery of tetrazolo-pyridazine-based small molecules as inhibitors of MACC1-driven cancer metastasis.
JO  - Biomedicine & pharmacotherapy
VL  - 168
SN  - 0753-3322
CY  - Amsterdam [u.a.]
PB  - Elsevier Science
M1  - DKFZ-2023-02147
SP  - 115698
PY  - 2023
AB  - 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.
KW  - Cancer metastasis (Other)
KW  - High-throughput screening (Other)
KW  - MACC1 (Other)
KW  - Tetrazolo-pyridazine (Other)
KW  - Transcriptional inhibitors (Other)
LB  - PUB:(DE-HGF)16
C6  - pmid:37865992
DO  - DOI:10.1016/j.biopha.2023.115698
UR  - https://inrepo02.dkfz.de/record/284947
ER  -