ABSTRACT
We recently reported the biological evaluations of monovalent IAP antagonist 7 with good potency (MDA-MB-231, IC50 = 19 nM). In an effort to increase cellular activity and improve favorable drug-like properties, we newly designed and synthesized bivalent analogues based on quinazoline structure of 7. Optimization of cellular potency and CYP inhibition led to the identification of 27, which showed dramatic increase of over 100-fold (IC50 = 0.14 nM) and caused substantial tumor regressions in MDA-MB-231 xenograft model. These results strongly support 27 as a promising bivalent antagonist for the development of an effective anti-tumor approaches.
Subject(s)
Antineoplastic Agents/pharmacology , Drug Design , Inhibitor of Apoptosis Proteins/antagonists & inhibitors , Quinazolines/pharmacology , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Dogs , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Humans , Inhibitor of Apoptosis Proteins/metabolism , Mice , Molecular Structure , Neoplasms, Experimental/drug therapy , Neoplasms, Experimental/metabolism , Neoplasms, Experimental/pathology , Quinazolines/chemical synthesis , Quinazolines/chemistry , Rats , Structure-Activity RelationshipABSTRACT
The importance of transforming growth factor beta-activated kinase 1 (TAK1) to cell survival has been demonstrated in many studies. TAK1 regulates signalling cascades, the NF-κB pathway and the mitogen-activated protein kinase (MAPK) pathway. TAK1 inhibitors can induce the apoptosis of cancerous cells, and irreversible inhibitors such as (5Z)-7-oxozeaenol are highly potent. However, they can react non-specifically with cysteine residues in proteins, which may have serious adverse effects. Reversible covalent inhibitors have been suggested as alternatives. We synthesised imidazopyridine derivatives as novel TAK1 inhibitors, which have 2-cyanoacrylamide moiety that can form reversible covalent bonding. A derivative with 2-cyano-3-(6-methylpyridin-2-yl)acrylamide (13h) exhibited potent TAK1 inhibitory activity with an IC50 of 27 nM. It showed a reversible reaction with ß-mercaptoethanol, which supports its potential as a reversible covalent inhibitor.
Subject(s)
Acrylamide/chemistry , Imidazoles/chemical synthesis , MAP Kinase Kinase Kinases/antagonists & inhibitors , Protein Kinase Inhibitors/chemical synthesis , Pyridines/chemical synthesis , Binding Sites , Humans , Imidazoles/metabolism , Mercaptoethanol/chemistry , Models, Molecular , NF-kappa B/metabolism , Protein Binding , Protein Kinase Inhibitors/metabolism , Pyridines/metabolism , Signal Transduction , Structure-Activity Relationship , Transcription Factor RelA , Zearalenone/analogs & derivatives , Zearalenone/chemistryABSTRACT
Transforming growth factor-ß activated kinase-1 (TAK1) is a potential therapeutic target for cancers and inflammatory diseases. We synthesized a series of novel imidazopyrazine derivatives, which were found to exhibit potent inhibitory effect against TAK1. Compound 22a, which possesses a good pharmacokinetic profile, showed excellent in vitro kinase activity and significant in vivo efficacy in mice xenografted with SW620, a KRAS-dependent colon cancer cell line.
Subject(s)
MAP Kinase Kinase Kinases/antagonists & inhibitors , Protein Kinase Inhibitors/chemistry , Pyrazines/therapeutic use , Animals , Cell Line, Tumor , Colonic Neoplasms/drug therapy , Colonic Neoplasms/pathology , Heterografts , Humans , Inflammation/drug therapy , Mice , Neoplasms/drug therapy , Pyrazines/chemical synthesis , Pyrazines/pharmacokinetics , Pyrazines/pharmacologyABSTRACT
Colony stimulating factor-1 receptor (CSF-1R or FMS) and it ligand, CSF-1, signaling regulates the differentiation and function of tumor-associated macrophages (TAMs) that play an important role in tumor progression. Derivatives of thieno[3,2-d]pyrimidine were synthesized and evaluated as kinase inhibitors of FMS. The most representative compound 21 showed strong activity (IC50â¯=â¯2â¯nM) against FMS kinase and served as candidate for proof of concept. Anti-tumor activity alone and/or in combination with paclitaxel was examined via a tumor cell growth inhibition assay and via an in vitro tumor invasion assay using human breast adenocarcinoma cells.