ABSTRACT
Tumor survival, metastases, chemoresistance, and escape from immune responses have been associated with inappropriate activation of STAT3 and/or STAT5 in various cancers, including solid tumors. Debio 0617B has been developed as a first-in-class kinase inhibitor with a unique profile targeting phospho-STAT3 (pSTAT3) and/or pSTAT5 in tumors through combined inhibition of JAK, SRC, ABL, and class III/V receptor tyrosine kinases (RTK). Debio 0617B showed dose-dependent inhibition of pSTAT3 in STAT3-activated carcinoma cell lines; Debio 0617B also showed potent antiproliferative activity in a panel of cancer cell lines and in patient-derived tumor xenografts tested in an in vitro clonogenic assay. Debio 0617B showed in vivo efficacy by inhibiting tumor growth in several mouse xenograft models. To increase in vivo efficacy and STAT3 inhibition, Debio 0617B was tested in combination with the EGFR inhibitor erlotinib in a non-small cell lung cancer xenograft model. To evaluate the impact of in vivo STAT3 blockade on metastases, Debio 0617B was tested in an orthotopic tumor model. Measurement of primary tumor weight and metastatic counts in lung tissue demonstrated therapeutic efficacy of Debio 0617B in this model. These data show potent activity of Debio 0617B on a broad spectrum of STAT3-driven solid tumors and synergistic activity in combination with EGFR inhibition. Mol Cancer Ther; 15(10); 2334-43. ©2016 AACR.
Subject(s)
Antineoplastic Agents/pharmacology , Janus Kinases/antagonists & inhibitors , Neoplasms/metabolism , Protein Kinase Inhibitors/pharmacology , Receptor Protein-Tyrosine Kinases/antagonists & inhibitors , STAT3 Transcription Factor/metabolism , src-Family Kinases/antagonists & inhibitors , Animals , Antineoplastic Agents/chemistry , Apoptosis/drug effects , Cell Line, Tumor , Disease Models, Animal , Drug Design , Humans , Janus Kinases/chemistry , Mice , Molecular Conformation , Molecular Docking Simulation , Molecular Dynamics Simulation , Neoplasm Metastasis , Neoplasms/drug therapy , Neoplasms/pathology , Protein Kinase Inhibitors/chemistry , Receptor Protein-Tyrosine Kinases/chemistry , Signal Transduction/drug effects , Tumor Burden/drug effects , Xenograft Model Antitumor Assays , src-Family Kinases/chemistryABSTRACT
Aromatase inhibition is the new standard of care for estrogen receptor positive breast cancer and has also potential for treatment of other diseases such as endometriosis. Simple and readily available 3-pyridyl arylethers and 1-aryl pyrrolo[2,3-c]pyridines recapitulating the key pharmacophore elements of Letrozole (1) are described and their structure-activity relationships are discussed. Potent and ligand efficient leads such as compound 23 (IC(50)=59nM on aromatase) have been identified.
Subject(s)
Aromatase Inhibitors/chemistry , Aromatase Inhibitors/pharmacology , Aromatase/metabolism , Breast Neoplasms/enzymology , Pyridines/chemistry , Pyridines/pharmacology , Pyrroles/chemistry , Pyrroles/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Breast Neoplasms/drug therapy , Female , Humans , Models, Molecular , Structure-Activity RelationshipABSTRACT
The recent discovery of an acquired activating point mutation in JAK2, substituting valine at amino acid position 617 for phenylalanine, has greatly improved our understanding of the molecular mechanism underlying chronic myeloproliferative neoplasms. Strikingly, the JAK2(V617F) mutation is found in nearly all patients suffering from polycythemia vera and in roughly every second patient suffering from essential thrombocythemia and primary myelofibrosis. Thus, JAK2 represents a promising target for the treatment of myeloproliferative neoplasms and considerable efforts are ongoing to discover and develop inhibitors of the kinase. Here, we report potent inhibition of JAK2(V617F) and JAK2 wild-type enzymes by a novel substituted quinoxaline, NVP-BSK805, which acts in an ATP-competitive manner. Within the JAK family, NVP-BSK805 displays more than 20-fold selectivity towards JAK2 in vitro, as well as excellent selectivity in broader kinase profiling. The compound blunts constitutive STAT5 phosphorylation in JAK2(V617F)-bearing cells, with concomitant suppression of cell proliferation and induction of apoptosis. In vivo, NVP-BSK805 exhibited good oral bioavailability and a long half-life. The inhibitor was efficacious in suppressing leukemic cell spreading and splenomegaly in a Ba/F3 JAK2(V617F) cell-driven mouse mechanistic model. Furthermore, NVP-BSK805 potently suppressed recombinant human erythropoietin-induced polycythemia and extramedullary erythropoiesis in mice and rats.
Subject(s)
Cell Proliferation/drug effects , Janus Kinase 2/antagonists & inhibitors , Polycythemia/prevention & control , Quinoxalines/pharmacology , Adenosine Triphosphate/pharmacology , Animals , Apoptosis/drug effects , Cell Line , Cell Line, Tumor , Erythropoiesis/drug effects , Humans , Janus Kinase 2/chemistry , Janus Kinase 2/genetics , K562 Cells , Mice , Mice, Inbred BALB C , Mice, SCID , Models, Molecular , Molecular Structure , Mutation , Phosphorylation/drug effects , Polycythemia/metabolism , Polycythemia/pathology , Protein Structure, Tertiary , Quinoxalines/chemistry , Rats , STAT5 Transcription Factor/metabolism , Splenomegaly/metabolism , Splenomegaly/pathology , Splenomegaly/prevention & controlABSTRACT
A series of novel benzoxazole derivatives has been designed and shown to exhibit attractive JAK2 inhibitory profiles in biochemical and cellular assays, capable of delivering compounds with favorable PK properties in rats. Synthesis and structure-activity relationship data are also provided.
Subject(s)
Benzoxazoles/chemistry , Janus Kinase 2/antagonists & inhibitors , Protein Kinase Inhibitors/chemistry , Administration, Oral , Animals , Benzoxazoles/chemical synthesis , Benzoxazoles/pharmacokinetics , Janus Kinase 2/metabolism , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/pharmacokinetics , Rats , Structure-Activity RelationshipABSTRACT
A pyrimidin-4-yl-urea motif forming a pseudo ring by intramolecular hydrogen bonding has been designed to mimic the pyrido[2,3-d]pyrimidin-7-one core structure of a well-established class of protein kinase inhibitors. Potent inhibition of a number of protein kinases was obtained with the first prototype compound synthesized to probe the design concept.
Subject(s)
Drug Design , Models, Molecular , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/pharmacology , Pyridones/chemistry , Pyridones/pharmacology , Pyrimidines/chemical synthesis , Pyrimidines/pharmacology , Urea/analogs & derivatives , Urea/chemical synthesis , Urea/pharmacology , Amino Acids/chemistry , Amino Acids/pharmacology , Molecular Conformation , Molecular Mimicry , Molecular Structure , Protein Kinase Inhibitors/chemistry , Pyrimidines/chemistry , Structure-Activity Relationship , Urea/chemistryABSTRACT
A series of beta-lactam derivatives has been designed and synthesized to inhibit the chymotrypsin-like activity of the human 20S proteasome. The most potent compounds of this new structural class of beta-subunit selective 20S proteasome inhibitors exhibit IC50 values in the low-nanomolar range and show good selectivity over the trypsin-like and post-glutamyl-peptide hydrolytic activities of the enzyme.
Subject(s)
Chymotrypsin/antagonists & inhibitors , Proteasome Inhibitors , Trypsin Inhibitors/chemical synthesis , Trypsin Inhibitors/pharmacology , beta-Lactams/chemical synthesis , beta-Lactams/pharmacology , Crystallography, X-Ray , Drug Design , Humans , Models, Molecular , Peptides/chemistry , Structure-Activity RelationshipABSTRACT
Proteasome inhibition is a therapeutic concept of current interest in anticancer research. We report here the design, synthesis, and biological characterization of prototypes of a new class of noncovalent proteasome inhibitors showing high activity in biochemical and cellular assays.
Subject(s)
Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Cysteine Proteinase Inhibitors/chemistry , Cysteine Proteinase Inhibitors/pharmacology , Multienzyme Complexes/antagonists & inhibitors , Binding Sites , Cell Division/drug effects , Cysteine Endopeptidases/chemistry , Cysteine Endopeptidases/metabolism , Cysteine Proteinase Inhibitors/metabolism , Drug Screening Assays, Antitumor/methods , Humans , Hydrogen Bonding , Inhibitory Concentration 50 , Models, Molecular , Molecular Structure , Multienzyme Complexes/chemistry , Multienzyme Complexes/metabolism , Oligopeptides/chemistry , Oligopeptides/metabolism , Oligopeptides/pharmacology , Proteasome Endopeptidase Complex , Structure-Activity Relationship , Tumor Cells, CulturedABSTRACT
We have identified 2-aminobenzylstatine derivatives that inhibit non-covalently the chymotrypsin-like activity of the human 20S proteasome. A structure-based optimisation approach has allowed us to improve the potency of this structural class of proteasome inhibitors from micromolar to nanomolar level. The new derivatives showed good selectivity against the trypsin-like and post-glutamyl-peptide hydrolytic activities of this enzyme.
