ABSTRACT
The Wnt/ß-catenin signaling pathway is aberrantly activated in colorectal (CRC) and many other cancers, and novel strategies for effectively targeting it may be needed due to its complexity. In this report, SM08502, a novel small molecule in clinical development for the treatment of solid tumors, was shown to reduce Wnt pathway signaling and gene expression through potent inhibition of CDC-like kinase (CLK) activity. SM08502 inhibited serine and arginine rich splicing factor (SRSF) phosphorylation and disrupted spliceosome activity, which was associated with inhibition of Wnt pathway-related gene and protein expression. Additionally, SM08502 induced the generation of splicing variants of Wnt pathway genes, suggesting that its mechanism for inhibition of gene expression includes effects on alternative splicing. Orally administered SM08502 significantly inhibited growth of gastrointestinal tumors and decreased SRSF phosphorylation and Wnt pathway gene expression in xenograft mouse models. These data implicate CLKs in the regulation of Wnt signaling and represent a novel strategy for inhibiting Wnt pathway gene expression in cancers. SM08502 is a first-in-class CLK inhibitor being investigated in a Phase 1 clinical trial for subjects with advanced solid tumors (NCT03355066).
Subject(s)
Colorectal Neoplasms/drug therapy , Protein Kinase Inhibitors/pharmacology , Protein Serine-Threonine Kinases/antagonists & inhibitors , Protein-Tyrosine Kinases/antagonists & inhibitors , Serine-Arginine Splicing Factors/metabolism , Stomach Neoplasms/drug therapy , Wnt Signaling Pathway/drug effects , Alternative Splicing/drug effects , Animals , Apoptosis/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Colorectal Neoplasms/pathology , Gene Expression Regulation, Neoplastic/drug effects , Gene Knockout Techniques , Humans , Inhibitory Concentration 50 , Mice , Phosphorylation/drug effects , Protein Kinase Inhibitors/therapeutic use , Protein Serine-Threonine Kinases/genetics , Protein Serine-Threonine Kinases/metabolism , Protein-Tyrosine Kinases/genetics , Protein-Tyrosine Kinases/metabolism , Rats , Stomach Neoplasms/pathology , Wnt Signaling Pathway/genetics , Xenograft Model Antitumor AssaysABSTRACT
Structure-activity relationship studies performed around 3-fluoro-5-(5-pyridin-2-yl-2H-tetrazol-2-yl)benzonitrile for the purpose of developing novel mGlu5 receptor antagonists are described. Synthesis of a series of four-ring tetrazoles led to the discovery of 3-[3-fluoro-5-(5-pyridin-2-yl-2H-tetrazol-2-yl)phenyl]-4-methylpyridine, a highly potent, brain penetrant, azole-based mGlu5 receptor antagonist.
Subject(s)
Anti-Anxiety Agents/pharmacokinetics , Nitriles/chemical synthesis , Pyridines/chemical synthesis , Receptors, Metabotropic Glutamate/antagonists & inhibitors , Tetrazoles/chemical synthesis , Administration, Oral , Animals , Anti-Anxiety Agents/administration & dosage , Anti-Anxiety Agents/chemical synthesis , Biological Availability , Molecular Structure , Nitriles/chemistry , Nitriles/pharmacokinetics , Pyridines/chemistry , Pyridines/pharmacokinetics , Rats , Receptor, Metabotropic Glutamate 5 , Structure-Activity Relationship , Tetrazoles/chemistry , Tetrazoles/pharmacokineticsABSTRACT
The synthesis and biological evaluation of a new series of amine-substituted 2-arylbenzimidazole-4-carboxamide inhibitors of the DNA-repair enzyme poly(ADP-ribose) polymerase-1 (PARP-1) is reported. The introduction of an amine substituent at the 2-aryl position is not detrimental to activity, with most inhibitors exhibiting K(i) values for PARP-1 inhibition in the low nanomolar range. Two compounds in this series were found to potentiate the cytotoxicity of the DNA-methylating agent temozolomide by 4-5-fold in a human colorectal cancer cell line.
Subject(s)
Amides/pharmacology , Antineoplastic Agents/chemical synthesis , Benzimidazoles/pharmacology , Dacarbazine/analogs & derivatives , Poly(ADP-ribose) Polymerase Inhibitors , Amides/chemical synthesis , Animals , Antineoplastic Agents/pharmacology , Benzimidazoles/chemical synthesis , Cell Line, Tumor , Cell Proliferation/drug effects , Colorectal Neoplasms/drug therapy , Colorectal Neoplasms/pathology , Dacarbazine/pharmacology , Drug Synergism , Humans , Lung Neoplasms/drug therapy , Lung Neoplasms/pathology , Structure-Activity Relationship , TemozolomideABSTRACT
Novel tricyclic benzimidazole carboxamide poly(ADP-ribose) polymerase-1 (PARP-1) inhibitors have been synthesized. Several compounds were found to be powerful chemopotentiators of temozolomide and topotecan in both A549 and LoVo cell lines. In vitro inhibition of PARP-1 was confirmed by direct measurement of NAD+ depletion and ADP-ribose polymer formation caused by chemically induced DNA damage.
Subject(s)
Benzimidazoles/chemical synthesis , Dacarbazine/analogs & derivatives , Enzyme Inhibitors/chemical synthesis , Heterocyclic Compounds, 3-Ring/chemical synthesis , Poly(ADP-ribose) Polymerase Inhibitors , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Benzimidazoles/chemistry , Benzimidazoles/pharmacology , Binding Sites , Cell Line , Crystallography, X-Ray , Dacarbazine/metabolism , Dacarbazine/pharmacology , Drug Resistance, Neoplasm , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Heterocyclic Compounds, 3-Ring/chemistry , Heterocyclic Compounds, 3-Ring/pharmacology , Humans , Models, Molecular , Prodrugs/chemical synthesis , Prodrugs/chemistry , Prodrugs/pharmacology , Stereoisomerism , Structure-Activity Relationship , Temozolomide , Topotecan/metabolism , Topotecan/pharmacologyABSTRACT
Utilizing the tools of parallel synthesis and structure-based design, a new class of Michael acceptor-containing, irreversible inhibitors of human rhinovirus 3C protease (HRV 3CP) was discovered. These inhibitors are shown to inhibit HRV-14 3CP with rates of inactivation ranging from 886 to 31 400 M(-1) sec(-1). These inhibitors exhibit antiviral activity when tested against HRV-14 infected H1-HeLa cells, with EC(50) values ranging from 1.94 to 0.15 microM. No cytotoxicity was observed at the limits of the assay concentration. A crystal structure of one of the more potent inhibitors covalently bound to HRV-2 3CP is detailed. These compounds were also tested against HRV serotypes other than type 14 and were found to have highly variable activities.
