ABSTRACT
Structural modifications of the left-hand side of compound 1 were identified which retained or improved potent binding to Bcl-2 and Bcl-xL in in vitro biochemical assays and had strong activity in an RS4;11 apoptotic cellular assay. For example, sulfoxide diastereomer 13 maintained good binding affinity and comparable cellular potency to 1 while improving aqueous solubility. The corresponding diastereomer (14) was significantly less potent in the cell, and docking studies suggest that this is due to a stereochemical preference for the RS versus SS sulfoxide. Appending a dimethylaminoethoxy side chain (27) adjacent to the benzylic position of the biphenyl moiety of 1 improved cellular activity by approximately three-fold, and this activity was corroborated in cell lines overexpressing Bcl-2 and Bcl-xL.
Subject(s)
Antineoplastic Agents/pharmacology , Proto-Oncogene Proteins c-bcl-2/antagonists & inhibitors , bcl-X Protein/antagonists & inhibitors , Aniline Compounds/chemistry , Aniline Compounds/pharmacology , Antineoplastic Agents/chemistry , Apoptosis/drug effects , Cell Line , Dose-Response Relationship, Drug , Humans , Models, Molecular , Molecular Structure , Proto-Oncogene Proteins c-bcl-2/metabolism , Solubility , Stereoisomerism , Structure-Activity Relationship , Sulfonamides/chemistry , Sulfonamides/pharmacology , bcl-X Protein/metabolismABSTRACT
A series of dimeric compounds based on the AVPI motif of Smac were designed and prepared as antagonists of the inhibitor of apoptosis proteins (IAPs). Optimization of cellular potency, physical properties, and pharmacokinetic parameters led to the identification of compound 14 (AZD5582), which binds potently to the BIR3 domains of cIAP1, cIAP2, and XIAP (IC50 = 15, 21, and 15 nM, respectively). This compound causes cIAP1 degradation and induces apoptosis in the MDA-MB-231 breast cancer cell line at subnanomolar concentrations in vitro. When administered intravenously to MDA-MB-231 xenograft-bearing mice, 14 results in cIAP1 degradation and caspase-3 cleavage within tumor cells and causes substantial tumor regressions following two weekly doses of 3.0 mg/kg. Antiproliferative effects are observed with 14 in only a small subset of the over 200 cancer cell lines examined, consistent with other published IAP inhibitors. As a result of its in vitro and in vivo profile, 14 was nominated as a candidate for clinical development.
Subject(s)
Alkynes/pharmacology , Antineoplastic Agents/pharmacology , Biomimetic Materials/pharmacology , Drug Discovery , Inhibitor of Apoptosis Proteins/antagonists & inhibitors , Neoplasms/drug therapy , Oligopeptides/pharmacology , Alkynes/chemical synthesis , Alkynes/chemistry , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Biomimetic Materials/chemical synthesis , Biomimetic Materials/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Dimerization , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Humans , Inhibitor of Apoptosis Proteins/metabolism , Mice , Molecular Conformation , Neoplasms/pathology , Oligopeptides/chemical synthesis , Oligopeptides/chemistry , Structure-Activity Relationship , Xenograft Model Antitumor AssaysABSTRACT
The potent and selective 3-amido-4-anilinoquinoline CSF-1R inhibitor AZ683 suffered from cardiovascular liabilities, which were linked to the off-target activities of the compound and ion channel activity in particular. Less basic and less lipophilic examples from both the quinoline and cinnoline series demonstrated cleaner secondary pharmacology profiles. Cinnoline 31 retained the required potency and oral PK profile, and was progressed through the safety screening cascade to be nominated into development as AZD7507.
Subject(s)
Aminoquinolines/chemical synthesis , Aminoquinolines/toxicity , Aniline Compounds/chemical synthesis , Aniline Compounds/toxicity , Cardiovascular System/drug effects , Enzyme Inhibitors/toxicity , Heterocyclic Compounds, 2-Ring/chemical synthesis , Heterocyclic Compounds, 2-Ring/toxicity , Receptor, Macrophage Colony-Stimulating Factor/antagonists & inhibitors , Aminoquinolines/chemistry , Aminoquinolines/pharmacology , Aniline Compounds/chemistry , Aniline Compounds/pharmacology , Animals , Cells, Cultured , Dogs , Dose-Response Relationship, Drug , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Guinea Pigs , Heterocyclic Compounds, 2-Ring/chemistry , Heterocyclic Compounds, 2-Ring/pharmacology , Humans , Inhibitory Concentration 50 , Molecular Structure , Myocytes, Cardiac/drug effects , RatsABSTRACT
3-Amido-4-anilinocinnolines have been identified as potent and highly selective inhibitors of CSF-1R. The synthesis and SAR of these compounds is reported, along with some physical property, pharmacokinetic and kinase selectivity data.
Subject(s)
Amides/chemical synthesis , Aniline Compounds/chemical synthesis , Heterocyclic Compounds, 2-Ring/chemical synthesis , Protein Kinase Inhibitors/chemical synthesis , Receptor, Macrophage Colony-Stimulating Factor/antagonists & inhibitors , Amides/chemistry , Aniline Compounds/chemistry , Animals , Dogs , Heterocyclic Compounds, 2-Ring/chemistry , Mice , Molecular Structure , Protein Kinase Inhibitors/chemistry , Rats , Structure-Activity RelationshipABSTRACT
Recognition of ligands by toll-like receptor (TLR) 2 requires interactions with other TLRs. TLRs form a combinatorial repertoire to discriminate between the diverse microbial ligands. Diversity results from extracellular and intracellular interactions of different TLRs. This paper demonstrates that TLR1 and TLR2 are required for ara-lipoarabinomannan- and tripalmitoyl cysteinyl lipopeptide-stimulated cytokine secretion from mononuclear cells. Confocal microscopy revealed that TLR1 and TLR2 cotranslationally form heterodimeric complexes on the cell surface and in the cytosol. Simultaneous cross-linking of both receptors resulted in ligand-independent signal transduction. Using chimeric TLRs, we found that expression of the extracellular domains along with simultaneous expression of the intracellular domains of both TLRs was necessary to achieve functional signaling. The domains from each receptor did not need to be contained within a single contiguous protein. Chimeric TLR analysis further defined the toll/IL-1R domains as the area of crucial intracellular TLR1-TLR2 interaction.
