ABSTRACT
Receptor tyrosine kinase therapies have proven to be efficacious in specific cancer patient populations; however, a significant limitation of tyrosine kinase inhibitor (TKI) treatment is the emergence of resistance mechanisms leading to a transient, partial, or complete lack of response. Combination therapies using agents with synergistic activity have potential to improve response and reduce acquired resistance. Chemoreagent or TKI treatment can lead to increased expression of hepatocyte growth factor (HGF) and/or MET, and this effect correlates with increased metastasis and poor prognosis. Despite MET's role in resistance and cancer biology, MET TKI monotherapy has yielded disappointing clinical responses. In this study, we describe the biological activity of a selective, oral MET TKI with slow off-rate and its synergistic antitumor effects when combined with an anti-HGF antibody. We evaluated the combined action of simultaneously neutralizing HGF ligand and inhibiting MET kinase activity in two cancer xenograft models that exhibit autocrine HGF/MET activation. The combination therapy results in additive antitumor activity in KP4 pancreatic tumors and synergistic activity in U-87MG glioblastoma tumors. Pharmacodynamic characterization of biomarkers that correlate with combination synergy reveal that monotherapies induce an increase in the total MET protein, whereas combination therapy significantly reduces total MET protein levels and phosphorylation of 4E-BP1. These results hold promise that dual targeting of HGF and MET by combining extracellular ligand inhibitors with intracellular MET TKIs could be an effective intervention strategy for cancer patients who have acquired resistance that is dependent on total MET protein. Mol Cancer Ther; 16(7); 1269-78. ©2017 AACR.
Subject(s)
Glioblastoma/drug therapy , Hepatocyte Growth Factor/genetics , Protein Kinase Inhibitors/administration & dosage , Proto-Oncogene Proteins c-met/genetics , Small Molecule Libraries/administration & dosage , Adaptor Proteins, Signal Transducing/genetics , Animals , Cell Cycle Proteins , Cell Line, Tumor , Drug Resistance, Neoplasm/genetics , Drug Synergism , Glioblastoma/genetics , Hepatocyte Growth Factor/antagonists & inhibitors , Humans , Mice , Phosphoproteins/genetics , Proto-Oncogene Proteins c-met/antagonists & inhibitors , Xenograft Model Antitumor AssaysABSTRACT
A series of macrocyclic derivatives has been designed and synthesized based on the X-ray co-crystal structures of pyrazolo[1,5-a] [1,3,5]triazines with corn CK2 (cCK2) protein. Bioassays demonstrated that these macrocyclic pyrazolo[1,5-a] [1,3,5]triazine compounds are potent CK2 inhibitors with K(i) around 1.0 nM and strongly inhibit cancer cell growth with IC(50) as low as approximately 100 nM.
Subject(s)
Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Casein Kinase II/antagonists & inhibitors , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Triazines/chemistry , Triazines/pharmacology , Animals , Antineoplastic Agents/chemical synthesis , Cell Line, Tumor , Colonic Neoplasms/pathology , Crystallography, X-Ray , Drug Design , Humans , Male , Molecular Conformation , Prostatic Neoplasms/pathology , Protein Kinase Inhibitors/chemical synthesis , Structure-Activity Relationship , Triazines/chemical synthesisABSTRACT
The structure-based design, synthesis, and anticancer activity of novel inhibitors of protein kinase CK2 are described. Using pyrazolo[1,5-a][1,3,5]triazine as the core scaffold, a structure-guided series of modifications provided pM inhibitors with microM-level cytotoxic activity in cell-based assays with prostate and colon cancer cell lines.
Subject(s)
Casein Kinase II/antagonists & inhibitors , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Binding Sites , Casein Kinase II/metabolism , Cell Line, Tumor , Crystallography, X-Ray , Drug Design , Humans , Models, Molecular , Molecular Structure , Protein Kinase Inhibitors/chemical synthesisABSTRACT
Fatty acid biosynthesis is essential for bacterial survival. Components of this biosynthetic pathway have been identified as attractive targets for the development of new antibacterial agents. FabH, beta-ketoacyl-ACP synthase III, is a particularly attractive target, since it is central to the initiation of fatty acid biosynthesis and is highly conserved among Gram-positive and -negative bacteria. Small molecules that inhibit FabH enzymatic activity have the potential to be candidates within a novel class of selective, nontoxic, broad-spectrum antibacterials. Using crystallographic structural information on these highly conserved active sites and structure based drug design principles, a benzoylaminobenzoic acid series of compounds was developed as potent inhibitors of FabH. This inhibitor class demonstrates strong antibacterial activity against Gram-positive and selected Gram-negative organisms.
Subject(s)
3-Oxoacyl-(Acyl-Carrier-Protein) Synthase/antagonists & inhibitors , Anti-Bacterial Agents/chemical synthesis , Bacterial Proteins/antagonists & inhibitors , 3-Oxoacyl-(Acyl-Carrier-Protein) Synthase/chemistry , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Bacterial Proteins/chemistry , Combinatorial Chemistry Techniques , Crystallization , Drug Design , Gram-Negative Bacteria/drug effects , Gram-Positive Bacteria/drug effects , Microbial Sensitivity Tests , Models, Molecular , Structure-Activity RelationshipABSTRACT
The structure-based design, synthesis, and biological activity of novel inhibitors of S-adenosyl homocysteine/methylthioadenosine (SAH/MTA) nucleosidase are described. Using 6-substituted purine and deaza purines as the core scaffolds, a systematic and structure guided series of modifications provided low nM inhibitors with broad-spectrum antimicrobial activity.
