Discovery of tetrazolo-pyridazine-based small molecules as inhibitors of MACC1-driven cancer metastasis
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 targetin...
| Main Authors: | , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2023-12-01
|
| Series: | Biomedicine & Pharmacotherapy |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S0753332223014968 |
| _version_ | 1797630677628223488 |
|---|---|
| author | Shixian Yan Paul Curtis Schöpe Joe Lewis Kerstin Putzker Ulrike Uhrig Edgar Specker Jens Peter von Kries Peter Lindemann Anahid Omran Hector E. Sanchez-Ibarra Anke Unger Mia-Lisa Zischinsky Bert Klebl Wolfgang Walther Marc Nazaré Dennis Kobelt Ulrike Stein |
| author_facet | Shixian Yan Paul Curtis Schöpe Joe Lewis Kerstin Putzker Ulrike Uhrig Edgar Specker Jens Peter von Kries Peter Lindemann Anahid Omran Hector E. Sanchez-Ibarra Anke Unger Mia-Lisa Zischinsky Bert Klebl Wolfgang Walther Marc Nazaré Dennis Kobelt Ulrike Stein |
| author_sort | Shixian Yan |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-11T11:10:33Z |
| format | Article |
| id | doaj.art-6858c7b995054e39a758cb5c3e16c24a |
| institution | Directory Open Access Journal |
| issn | 0753-3322 |
| language | English |
| last_indexed | 2024-03-11T11:10:33Z |
| publishDate | 2023-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Biomedicine & Pharmacotherapy |
| spelling | doaj.art-6858c7b995054e39a758cb5c3e16c24a2023-11-12T04:38:57ZengElsevierBiomedicine & Pharmacotherapy0753-33222023-12-01168115698Discovery of tetrazolo-pyridazine-based small molecules as inhibitors of MACC1-driven cancer metastasisShixian Yan0Paul Curtis Schöpe1Joe Lewis2Kerstin Putzker3Ulrike Uhrig4Edgar Specker5Jens Peter von Kries6Peter Lindemann7Anahid Omran8Hector E. Sanchez-Ibarra9Anke Unger10Mia-Lisa Zischinsky11Bert Klebl12Wolfgang Walther13Marc Nazaré14Dennis Kobelt15Ulrike Stein16Experimental and Clinical Research Center, Charité - Universitätsmedizin Berlin, and Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Str. 10, 13125 Berlin, GermanyExperimental and Clinical Research Center, Charité - Universitätsmedizin Berlin, and Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Str. 10, 13125 Berlin, GermanyThe European Molecular Biology Laboratory, EMBL, Meyerhofstraße 1, 69120 Heidelberg, GermanyThe European Molecular Biology Laboratory, EMBL, Meyerhofstraße 1, 69120 Heidelberg, GermanyThe European Molecular Biology Laboratory, EMBL, Meyerhofstraße 1, 69120 Heidelberg, GermanyLeibniz-Forschungsinstitut für Molekulare Pharmakologie, FMP, Robert-Rössle-Str. 10, 13125 Berlin, GermanyLeibniz-Forschungsinstitut für Molekulare Pharmakologie, FMP, Robert-Rössle-Str. 10, 13125 Berlin, GermanyLeibniz-Forschungsinstitut für Molekulare Pharmakologie, FMP, Robert-Rössle-Str. 10, 13125 Berlin, GermanyLeibniz-Forschungsinstitut für Molekulare Pharmakologie, FMP, Robert-Rössle-Str. 10, 13125 Berlin, GermanyExperimental and Clinical Research Center, Charité - Universitätsmedizin Berlin, and Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Str. 10, 13125 Berlin, GermanyLead Discovery Center GmbH, LDC, Otto-Hahn-Str. 15, 44227 Dortmund, GermanyLead Discovery Center GmbH, LDC, Otto-Hahn-Str. 15, 44227 Dortmund, GermanyLead Discovery Center GmbH, LDC, Otto-Hahn-Str. 15, 44227 Dortmund, GermanyExperimental and Clinical Research Center, Charité - Universitätsmedizin Berlin, and Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Str. 10, 13125 Berlin, GermanyLeibniz-Forschungsinstitut für Molekulare Pharmakologie, FMP, Robert-Rössle-Str. 10, 13125 Berlin, GermanyExperimental and Clinical Research Center, Charité - Universitätsmedizin Berlin, and Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Str. 10, 13125 Berlin, Germany; German Cancer Consortium (DKTK Partnersite Berlin), Deutsches Krebsforschungszentrum (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, GermanyExperimental and Clinical Research Center, Charité - Universitätsmedizin Berlin, and Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Str. 10, 13125 Berlin, Germany; German Cancer Consortium (DKTK Partnersite Berlin), Deutsches Krebsforschungszentrum (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany; Corresponding author at: Experimental and Clinical Research Center, Charité - Universitätsmedizin Berlin, and Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Str. 10, 13125 Berlin, Germany.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.http://www.sciencedirect.com/science/article/pii/S0753332223014968High-throughput screeningCancer metastasisMACC1Transcriptional inhibitorsTetrazolo-pyridazine |
| spellingShingle | Shixian Yan Paul Curtis Schöpe Joe Lewis Kerstin Putzker Ulrike Uhrig Edgar Specker Jens Peter von Kries Peter Lindemann Anahid Omran Hector E. Sanchez-Ibarra Anke Unger Mia-Lisa Zischinsky Bert Klebl Wolfgang Walther Marc Nazaré Dennis Kobelt Ulrike Stein Discovery of tetrazolo-pyridazine-based small molecules as inhibitors of MACC1-driven cancer metastasis Biomedicine & Pharmacotherapy High-throughput screening Cancer metastasis MACC1 Transcriptional inhibitors Tetrazolo-pyridazine |
| title | Discovery of tetrazolo-pyridazine-based small molecules as inhibitors of MACC1-driven cancer metastasis |
| title_full | Discovery of tetrazolo-pyridazine-based small molecules as inhibitors of MACC1-driven cancer metastasis |
| title_fullStr | Discovery of tetrazolo-pyridazine-based small molecules as inhibitors of MACC1-driven cancer metastasis |
| title_full_unstemmed | Discovery of tetrazolo-pyridazine-based small molecules as inhibitors of MACC1-driven cancer metastasis |
| title_short | Discovery of tetrazolo-pyridazine-based small molecules as inhibitors of MACC1-driven cancer metastasis |
| title_sort | discovery of tetrazolo pyridazine based small molecules as inhibitors of macc1 driven cancer metastasis |
| topic | High-throughput screening Cancer metastasis MACC1 Transcriptional inhibitors Tetrazolo-pyridazine |
| url | http://www.sciencedirect.com/science/article/pii/S0753332223014968 |
| work_keys_str_mv | AT shixianyan discoveryoftetrazolopyridazinebasedsmallmoleculesasinhibitorsofmacc1drivencancermetastasis AT paulcurtisschope discoveryoftetrazolopyridazinebasedsmallmoleculesasinhibitorsofmacc1drivencancermetastasis AT joelewis discoveryoftetrazolopyridazinebasedsmallmoleculesasinhibitorsofmacc1drivencancermetastasis AT kerstinputzker discoveryoftetrazolopyridazinebasedsmallmoleculesasinhibitorsofmacc1drivencancermetastasis AT ulrikeuhrig discoveryoftetrazolopyridazinebasedsmallmoleculesasinhibitorsofmacc1drivencancermetastasis AT edgarspecker discoveryoftetrazolopyridazinebasedsmallmoleculesasinhibitorsofmacc1drivencancermetastasis AT jenspetervonkries discoveryoftetrazolopyridazinebasedsmallmoleculesasinhibitorsofmacc1drivencancermetastasis AT peterlindemann discoveryoftetrazolopyridazinebasedsmallmoleculesasinhibitorsofmacc1drivencancermetastasis AT anahidomran discoveryoftetrazolopyridazinebasedsmallmoleculesasinhibitorsofmacc1drivencancermetastasis AT hectoresanchezibarra discoveryoftetrazolopyridazinebasedsmallmoleculesasinhibitorsofmacc1drivencancermetastasis AT ankeunger discoveryoftetrazolopyridazinebasedsmallmoleculesasinhibitorsofmacc1drivencancermetastasis AT mialisazischinsky discoveryoftetrazolopyridazinebasedsmallmoleculesasinhibitorsofmacc1drivencancermetastasis AT bertklebl discoveryoftetrazolopyridazinebasedsmallmoleculesasinhibitorsofmacc1drivencancermetastasis AT wolfgangwalther discoveryoftetrazolopyridazinebasedsmallmoleculesasinhibitorsofmacc1drivencancermetastasis AT marcnazare discoveryoftetrazolopyridazinebasedsmallmoleculesasinhibitorsofmacc1drivencancermetastasis AT denniskobelt discoveryoftetrazolopyridazinebasedsmallmoleculesasinhibitorsofmacc1drivencancermetastasis AT ulrikestein discoveryoftetrazolopyridazinebasedsmallmoleculesasinhibitorsofmacc1drivencancermetastasis |