LIVIVO - Search results -

Search results

Result 1 - 8 of total 8

Search options

Article ; Online: Stereoselective synthesis of 3,4-dihydropyrrolo[1,2-a]pyrazin-1(2H)-one derivatives as PIM kinase inhibitors inspired from marine alkaloids.

Casuscelli, Francesco / Ardini, Elena / Avanzi, Nilla / Badari, Alessandra / Casale, Elena / Disingrini, Teresa / Donati, Daniele / Ermoli, Antonella / Felder, Eduard R / Galvani, Arturo / Isacchi, Antonella / Menichincheri, Maria / Montemartini, Marisa / Orrenius, Christian / Piutti, Claudia / Salom, Barbara / Papeo, Gianluca

Chirality

2022 Volume 34, Issue 11, Page(s) 1437–1452

Abstract: We previously demonstrated that natural product-inspired 3,4-dihydropyrrolo[1,2-a]pyrazin-1(2H)-ones derivatives delivered potent and selective PIM kinases inhibitors however with non-optimal ADME/PK properties and modest oral bioavailability. Herein, we ...

Abstract	We previously demonstrated that natural product-inspired 3,4-dihydropyrrolo[1,2-a]pyrazin-1(2H)-ones derivatives delivered potent and selective PIM kinases inhibitors however with non-optimal ADME/PK properties and modest oral bioavailability. Herein, we describe a structure-based scaffold decoration and a stereoselective approach to this chemical class. The synthesis, structure-activity relationship studies, chiral analysis, and pharmacokinetic data of compounds from this inhibitor class are presented herein. Compound 20c demonstrated excellent potency on PIM1 and PIM2 with exquisite kinases selectivity and PK properties that efficiently and dose-dependently promoted c-Myc degradation and appear to be promising lead compounds for further development.
MeSH term(s)	Alkaloids/pharmacology ; Antineoplastic Agents/pharmacology ; Cell Line, Tumor ; Protein Kinase Inhibitors/chemistry ; Protein Kinase Inhibitors/pharmacology ; Proto-Oncogene Proteins c-pim-1/chemistry ; Proto-Oncogene Proteins c-pim-1/metabolism ; Stereoisomerism ; Structure-Activity Relationship
Chemical Substances	Alkaloids ; Antineoplastic Agents ; Protein Kinase Inhibitors ; Proto-Oncogene Proteins c-pim-1 (EC 2.7.11.1) ; proto-oncogene proteins pim (EC 2.7.11.1)
Language	English
Publishing date	2022-08-12
Publishing country	United States
Document type	Journal Article
ZDB-ID	1011639-4
ISSN	1520-636X ; 0899-0042
ISSN (online)	1520-636X
ISSN	0899-0042
DOI	10.1002/chir.23501
Database	MEDical Literature Analysis and Retrieval System OnLINE

Full text online

Accessible to users with ZB MED library card

In stock of ZB MED Cologne/Königswinter

Zs.A 2594: Show issues

Location:
Je nach Verfügbarkeit (siehe Angabe bei Bestand)
bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
Jg. 1995 - 2021: Lesesall (2.OG)
ab Jg. 2022: Lesesaal (EG)

Order via subito

This service is chargeable due to the Delivery terms set by subito. Orders including an article and supplementary material will be classified as separate orders. In these cases, fees will be demanded for each order.

Details ▾

Article ; Online: The generation of purinome-targeted libraries as a means to diversify ATP-mimetic chemical classes for lead finding.

Felder, Eduard R / Badari, Alessandra / Disingrini, Teresa / Mantegani, Sergio / Orrenius, Christian / Avanzi, Nilla / Isacchi, Antonella / Salom, Barbara

Molecular diversity

2012 Volume 16, Issue 1, Page(s) 27–51

Abstract: The generation of novel chemotypes in support of our oncology research projects expanded in recent years from a canonical design of kinase-targeted compound libraries to a broader interpretation of purinome-targeted libraries (PTL) addressing the ... ...

Abstract	The generation of novel chemotypes in support of our oncology research projects expanded in recent years from a canonical design of kinase-targeted compound libraries to a broader interpretation of purinome-targeted libraries (PTL) addressing the specificity of cancer relevant targets such as kinases and ATPases. Successful screening of structurally diverse ATP-binding targets requires compound libraries covering multiple design elements, which may include phosphate surrogate moieties in ATPase inhibitors or far reaching lipophilic residues stabilizing inactive kinase conformations. Here, we exemplify the design and preparation of drug-like combinatorial libraries and report significantly enhanced screening performance on purinomic targets. We compared overall hit rates of PTL with a simultaneously tested unbiased collection of 200,000 compounds and found consistent superiority of the targeted libraries in all cases. We also analyzed the performance of the largest targeted libraries in comparison with each other and often found striking differences in how a specific target responds to various chemotypes and to whole collections.
MeSH term(s)	Adenosine Triphosphate/analogs & derivatives ; Binding Sites ; Combinatorial Chemistry Techniques/methods ; Databases as Topic ; Drug Design ; High-Throughput Screening Assays ; Models, Molecular ; Protein Kinase Inhibitors/analysis ; Protein Kinase Inhibitors/pharmacology ; Protein Kinases/metabolism ; Pyrazoles/chemistry ; Reference Standards ; Small Molecule Libraries/analysis ; Small Molecule Libraries/pharmacology
Chemical Substances	Protein Kinase Inhibitors ; Pyrazoles ; Small Molecule Libraries ; Adenosine Triphosphate (8L70Q75FXE) ; Protein Kinases (EC 2.7.-)
Language	English
Publishing date	2012-02-15
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1376507-3
ISSN	1573-501X ; 1381-1991
ISSN (online)	1573-501X
ISSN	1381-1991
DOI	10.1007/s11030-012-9361-6
Database	MEDical Literature Analysis and Retrieval System OnLINE

Full text online

Accessible to users with ZB MED library card

In stock of ZB MED Cologne/Königswinter

Zs.A 4946: Show issues

Location:
Je nach Verfügbarkeit (siehe Angabe bei Bestand)
bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
Jg. 1995 - 2021: Lesesall (2.OG)
ab Jg. 2022: Lesesaal (EG)

Order via subito

Details ▾

Article ; Online: Establishment and genomic characterization of the new chordoma cell line Chor-IN-1.

Bosotti, Roberta / Magnaghi, Paola / Di Bella, Sebastiano / Cozzi, Liviana / Cusi, Carlo / Bozzi, Fabio / Beltrami, Nicola / Carapezza, Giovanni / Ballinari, Dario / Amboldi, Nadia / Lupi, Rosita / Somaschini, Alessio / Raddrizzani, Laura / Salom, Barbara / Galvani, Arturo / Stacchiotti, Silvia / Tamborini, Elena / Isacchi, Antonella

Scientific reports

2017 Volume 7, Issue 1, Page(s) 9226

Abstract: Chordomas are rare, slowly growing tumors with high medical need, arising in the axial skeleton from notochord remnants. The transcription factor "brachyury" represents a distinctive molecular marker and a key oncogenic driver of chordomas. Tyrosine ... ...

Abstract	Chordomas are rare, slowly growing tumors with high medical need, arising in the axial skeleton from notochord remnants. The transcription factor "brachyury" represents a distinctive molecular marker and a key oncogenic driver of chordomas. Tyrosine kinase receptors are also expressed, but so far kinase inhibitors have not shown clear clinical efficacy in chordoma patients. The need for effective therapies is extremely high, but the paucity of established chordoma cell lines has limited preclinical research. Here we describe the isolation of the new Chor-IN-1 cell line from a recurrent sacral chordoma and its characterization as compared to other chordoma cell lines. Chor-IN-1 displays genomic identity to the tumor of origin and has morphological features, growth characteristics and chromosomal abnormalities typical of chordoma, with expression of brachyury and other relevant biomarkers. Chor-IN-1 gene variants, copy number alterations and kinome gene expression were analyzed in comparison to other four chordoma cell lines, generating large scale DNA and mRNA genomic data that can be exploited for the identification of novel pharmacological targets and candidate predictive biomarkers of drug sensitivity in chordoma. The establishment of this new, well characterized chordoma cell line provides a useful tool for the identification of drugs active in chordoma.
MeSH term(s)	Biopsy ; Cell Line, Tumor ; Chordoma/genetics ; Chordoma/metabolism ; Chordoma/pathology ; Chromosome Aberrations ; DNA Copy Number Variations ; Gene Expression Regulation, Neoplastic ; Genomics/methods ; Humans ; Immunohistochemistry ; Karyotype ; Male ; Middle Aged
Language	English
Publishing date	2017-08-23
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-017-10044-3
Database	MEDical Literature Analysis and Retrieval System OnLINE

Order via subito

Article ; Online: Afatinib Is a New Therapeutic Approach in Chordoma with a Unique Ability to Target EGFR and Brachyury.

Magnaghi, Paola / Salom, Barbara / Cozzi, Liviana / Amboldi, Nadia / Ballinari, Dario / Tamborini, Elena / Gasparri, Fabio / Montagnoli, Alessia / Raddrizzani, Laura / Somaschini, Alessio / Bosotti, Roberta / Orrenius, Christian / Bozzi, Fabio / Pilotti, Silvana / Galvani, Arturo / Sommer, Josh / Stacchiotti, Silvia / Isacchi, Antonella

Molecular cancer therapeutics

2017 Volume 17, Issue 3, Page(s) 603–613

Abstract: Chordomas are rare bone tumors with no approved therapy. These tumors express several activated tyrosine kinase receptors, which prompted attempts to treat patients with tyrosine kinase inhibitors. Although clinical benefit was observed in phase II ... ...

Abstract	Chordomas are rare bone tumors with no approved therapy. These tumors express several activated tyrosine kinase receptors, which prompted attempts to treat patients with tyrosine kinase inhibitors. Although clinical benefit was observed in phase II clinical trials with imatinib and sorafenib, and sporadically also with EGFR inhibitors, therapies evaluated to date have shown modest activity. With the goal of identifying new drugs with immediate therapeutic potential for chordoma patients, we collected clinically approved drugs and other advanced inhibitors of MET, PDGFRβ, and EGFR tyrosine kinases, and assessed their antiproliferative activity against a panel of chordoma cell lines. Chordoma cell lines were not responsive to MET and PDGFRβ inhibitors. U-CH1 and UM-Chor1 were sensitive to all EGFR inhibitors, whereas the remaining cell lines were generally insensitive to these drugs. Afatinib was the only EGFR inhibitor with activity across the chordoma panel. We then investigated the molecular mechanisms behind the responses observed and found that the antiproliferative IC
MeSH term(s)	Afatinib/therapeutic use ; Animals ; Bone Neoplasms/drug therapy ; Bone Neoplasms/genetics ; Bone Neoplasms/metabolism ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Chordoma/drug therapy ; Chordoma/genetics ; Chordoma/metabolism ; ErbB Receptors/antagonists & inhibitors ; ErbB Receptors/genetics ; ErbB Receptors/metabolism ; Fetal Proteins/antagonists & inhibitors ; Fetal Proteins/genetics ; Fetal Proteins/metabolism ; Gene Expression Regulation, Neoplastic/drug effects ; Humans ; Mice, Nude ; Phosphorylation/drug effects ; Protein Kinase Inhibitors/therapeutic use ; T-Box Domain Proteins/antagonists & inhibitors ; T-Box Domain Proteins/genetics ; T-Box Domain Proteins/metabolism ; Tumor Burden/drug effects ; Tumor Burden/genetics ; Xenograft Model Antitumor Assays
Chemical Substances	Fetal Proteins ; Protein Kinase Inhibitors ; T-Box Domain Proteins ; Afatinib (41UD74L59M) ; ErbB Receptors (EC 2.7.10.1) ; Brachyury protein (EQ43SC3GDB)
Language	English
Publishing date	2017-12-13
Publishing country	United States
Document type	Journal Article
ZDB-ID	2063563-1
ISSN	1538-8514 ; 1535-7163
ISSN (online)	1538-8514
ISSN	1535-7163
DOI	10.1158/1535-7163.MCT-17-0324
Database	MEDical Literature Analysis and Retrieval System OnLINE

In stock of ZB MED Cologne/Königswinter

Zs.A 5750: Show issues

Location:
Je nach Verfügbarkeit (siehe Angabe bei Bestand)
bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
Jg. 1995 - 2021: Lesesall (2.OG)
ab Jg. 2022: Lesesaal (EG)

Order via subito

Details ▾
- See ZB MED holdings
- Order with fees

Article ; Online: Discovery and optimization of pyrrolo[1,2-a]pyrazinones leads to novel and selective inhibitors of PIM kinases.

Casuscelli, Francesco / Ardini, Elena / Avanzi, Nilla / Casale, Elena / Cervi, Giovanni / D'Anello, Matteo / Donati, Daniele / Faiardi, Daniela / Ferguson, Ronald D / Fogliatto, Gianpaolo / Galvani, Arturo / Marsiglio, Aurelio / Mirizzi, Danilo G / Montemartini, Marisa / Orrenius, Christian / Papeo, Gianluca / Piutti, Claudia / Salom, Barbara / Felder, Eduard R

Bioorganic & medicinal chemistry

2013 Volume 21, Issue 23, Page(s) 7364–7380

Abstract: A novel series of PIM inhibitors was derived from a combined effort in natural product-inspired library generation and screening. The novel pyrrolo[1,2-a]pyrazinones initial hits are inhibitors of PIM isoforms with IC50 values in the low micromolar range. ...

Abstract	A novel series of PIM inhibitors was derived from a combined effort in natural product-inspired library generation and screening. The novel pyrrolo[1,2-a]pyrazinones initial hits are inhibitors of PIM isoforms with IC50 values in the low micromolar range. The application of a rational optimization strategy, guided by the determination of the crystal structure of the complex in the kinase domain of PIM1 with compound 1, led to the discovery of compound 15a, which is a potent PIM kinases inhibitor exhibiting excellent selectivity against a large panel of kinases, representative of each family. The synthesis, structure-activity relationship studies, and pharmacokinetic data of compounds from this inhibitor class are presented herein. Furthermore, the cellular activities including inhibition of cell growth and modulation of downstream targets are also described.
MeSH term(s)	Drug Discovery ; Humans ; Molecular Docking Simulation ; Protein Kinase Inhibitors/chemical synthesis ; Protein Kinase Inhibitors/chemistry ; Protein Kinase Inhibitors/pharmacology ; Protein Structure, Tertiary ; Proto-Oncogene Proteins c-pim-1/antagonists & inhibitors ; Proto-Oncogene Proteins c-pim-1/chemistry ; Proto-Oncogene Proteins c-pim-1/metabolism ; Pyrazines/chemical synthesis ; Pyrazines/chemistry ; Pyrazines/pharmacology
Chemical Substances	Protein Kinase Inhibitors ; Pyrazines ; Proto-Oncogene Proteins c-pim-1 (EC 2.7.11.1) ; proto-oncogene proteins pim (EC 2.7.11.1)
Language	English
Publishing date	2013-12-01
Publishing country	England
Document type	Journal Article
ZDB-ID	1161284-8
ISSN	1464-3391 ; 0968-0896
ISSN (online)	1464-3391
ISSN	0968-0896
DOI	10.1016/j.bmc.2013.09.054
Database	MEDical Literature Analysis and Retrieval System OnLINE

Full text online

Accessible to users with ZB MED library card

In stock of ZB MED Cologne/Königswinter

Zs.A 3815: Show issues

Location:
Je nach Verfügbarkeit (siehe Angabe bei Bestand)
bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
Jg. 1995 - 2021: Lesesall (2.OG)
ab Jg. 2022: Lesesaal (EG)

Order via subito

Details ▾

Article: Discovery and optimization of pyrrolo[1,2-a]pyrazinones leads to novel and selective inhibitors of PIM kinases

Casuscelli, Francesco / Ardini, Elena / Avanzi, Nilla / Casale, Elena / Cervi, Giovanni / D’Anello, Matteo / Donati, Daniele / Faiardi, Daniela / Ferguson, Ronald D / Fogliatto, Gianpaolo / Galvani, Arturo / Marsiglio, Aurelio / Mirizzi, Danilo G / Montemartini, Marisa / Orrenius, Christian / Papeo, Gianluca / Piutti, Claudia / Salom, Barbara / Felder, Eduard R

Bioorganic & medicinal chemistry. 2013 Dec. 1, v. 21, no. 23

2013

Abstract	A novel series of PIM inhibitors was derived from a combined effort in natural product-inspired library generation and screening. The novel pyrrolo[1,2-a]pyrazinones initial hits are inhibitors of PIM isoforms with IC₅₀ values in the low micromolar range. The application of a rational optimization strategy, guided by the determination of the crystal structure of the complex in the kinase domain of PIM1 with compound 1, led to the discovery of compound 15a, which is a potent PIM kinases inhibitor exhibiting excellent selectivity against a large panel of kinases, representative of each family. The synthesis, structure–activity relationship studies, and pharmacokinetic data of compounds from this inhibitor class are presented herein. Furthermore, the cellular activities including inhibition of cell growth and modulation of downstream targets are also described.
Keywords	cell growth ; crystal structure ; inhibitory concentration 50 ; pharmacokinetics ; phosphotransferases (kinases) ; screening ; structure-activity relationships
Language	English
Dates of publication	2013-1201
Size	p. 7364-7380.
Publishing place	Elsevier Ltd
Document type	Article
ZDB-ID	1161284-8
ISSN	1464-3391 ; 0968-0896
ISSN (online)	1464-3391
ISSN	0968-0896
DOI	10.1016/j.bmc.2013.09.054
Database	NAL-Catalogue (AGRICOLA)

Full text online

Accessible to users with ZB MED library card

In stock of ZB MED Cologne/Königswinter

Zs.A 3815: Show issues

Location:
Je nach Verfügbarkeit (siehe Angabe bei Bestand)
bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
Jg. 1995 - 2021: Lesesall (2.OG)
ab Jg. 2022: Lesesaal (EG)

Order via subito

Details ▾

Article ; Online: Discovery of 2-(cyclohexylmethylamino)pyrimidines as a new class of reversible valosine containing protein inhibitors.

Cervi, Giovanni / Magnaghi, Paola / Asa, Daniela / Avanzi, Nilla / Badari, Alessandra / Borghi, Daniela / Caruso, Michele / Cirla, Alessandra / Cozzi, Liviana / Felder, Eduard / Galvani, Arturo / Gasparri, Fabio / Lomolino, Antonio / Magnuson, Steven / Malgesini, Beatrice / Motto, Ilaria / Pasi, Maurizio / Rizzi, Simona / Salom, Barbara /

Sorrentino, Graziella / Troiani, Sonia / Valsasina, Barbara / O'Brien, Thomas / Isacchi, Antonella / Donati, Daniele / D'Alessio, Roberto

Journal of medicinal chemistry

2014 Volume 57, Issue 24, Page(s) 10443–10454

Abstract: Valosine-containing protein (VCP), also known as p97 or cdc48 in yeast, is a highly abundant protein belonging to the AAA ATPase family involved in a number of essential cellular functions, including ubiquitin-proteasome mediated protein degradation, ... ...

Abstract	Valosine-containing protein (VCP), also known as p97 or cdc48 in yeast, is a highly abundant protein belonging to the AAA ATPase family involved in a number of essential cellular functions, including ubiquitin-proteasome mediated protein degradation, Golgi reassembly, transcription activation, and cell cycle control. Altered expression of VCP has been detected in many cancer types sometimes associated with poor prognosis. Furthermore, VCP mutations are causative of some neurodegenerative disorders. In this paper we report the discovery, synthesis, and structure-activity relationships of substituted 2-aminopyrimidines, representing a new class of reversible VCP inhibitors. This class of compounds, identified in a HTS campaign against recombinant VCP, has been progressively expanded and manipulated to increase biochemical potency and gain cellular activity.
MeSH term(s)	Adenosine Triphosphatases/antagonists & inhibitors ; Adenosine Triphosphatases/metabolism ; Cell Cycle Proteins/antagonists & inhibitors ; Cell Cycle Proteins/metabolism ; Cell Proliferation/drug effects ; Drug Discovery ; Enzyme Inhibitors/chemistry ; Enzyme Inhibitors/pharmacology ; HCT116 Cells ; Humans ; Models, Molecular ; Molecular Structure ; Pyrimidines/chemistry ; Pyrimidines/pharmacology ; Structure-Activity Relationship ; Valosin Containing Protein
Chemical Substances	Cell Cycle Proteins ; Enzyme Inhibitors ; Pyrimidines ; Adenosine Triphosphatases (EC 3.6.1.-) ; VCP protein, human (EC 3.6.4.6) ; Valosin Containing Protein (EC 3.6.4.6) ; pyrimidine (K8CXK5Q32L)
Language	English
Publishing date	2014-12-26
Publishing country	United States
Document type	Journal Article
ZDB-ID	218133-2
ISSN	1520-4804 ; 0022-2623
ISSN (online)	1520-4804
ISSN	0022-2623
DOI	10.1021/jm501313x
Database	MEDical Literature Analysis and Retrieval System OnLINE

In stock of ZB MED Cologne/Königswinter

Zs.B 151: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular ab Jg. 2022: Lesesaal (EG)
Zs.MB 1: Show issues

Order via subito

Details ▾
- See ZB MED holdings
- Order with fees

Article: Discovery and optimization of pyrrolo[1,2-a]pyrazinones leads to novel and selective inhibitors of PIM kinases

Casuscelli, Francesco / Ardini, Elena / Avanzi, Nilla / Casale, Elena / Cervi, Giovanni / D’Anello, Matteo / Donati, Daniele / Faiardi, Daniela / Ferguson, Ronald D. / Fogliatto, Gianpaolo / Galvani, Arturo / Marsiglio, Aurelio / Mirizzi, Danilo G. / Montemartini, Marisa / Orrenius, Christian / Papeo, Gianluca / Piutti, Claudia / Salom, Barbara / Felder, Eduard R.

Bioorganic & medicinal chemistry

Volume v. 21,, Issue no. 2

Abstract	A novel series of PIM inhibitors was derived from a combined effort in natural product-inspired library generation and screening. The novel pyrrolo[1,2-a]pyrazinones initial hits are inhibitors of PIM isoforms with IC₅₀ values in the low micromolar range. The application of a rational optimization strategy, guided by the determination of the crystal structure of the complex in the kinase domain of PIM1 with compound 1, led to the discovery of compound 15a, which is a potent PIM kinases inhibitor exhibiting excellent selectivity against a large panel of kinases, representative of each family. The synthesis, structure–activity relationship studies, and pharmacokinetic data of compounds from this inhibitor class are presented herein. Furthermore, the cellular activities including inhibition of cell growth and modulation of downstream targets are also described.
Keywords	structure-activity relationships ; screening ; phosphotransferases (kinases) ; inhibitory concentration 50 ; crystal structure ; cell growth ; pharmacokinetics
Language	English
Document type	Article
ISSN	0968-0896
Database	AGRIS - International Information System for the Agricultural Sciences and Technology

Order via subito

Inter-library loan at ZB MED

Your chosen title can be delivered directly to ZB MED Cologne location if you are registered as a user at ZB MED Cologne.

To top

Full text online

More links

Kategorien

In stock of ZB MED Cologne/Königswinter

Order via subito

Full text online

More links

Kategorien

In stock of ZB MED Cologne/Königswinter

Order via subito

More links

Kategorien

Order via subito

More links

Kategorien

In stock of ZB MED Cologne/Königswinter

Order via subito

Full text online

More links

Kategorien

In stock of ZB MED Cologne/Königswinter

Order via subito

Full text online

More links

Kategorien

In stock of ZB MED Cologne/Königswinter

Order via subito

More links

Kategorien

In stock of ZB MED Cologne/Königswinter

Order via subito

More links

Kategorien

Order via subito

Inter-library loan at ZB MED