ABSTRACT
Discovery of a new class of DFG-out p38α kinase inhibitors with no hinge interaction is described. A computationally assisted, virtual fragment-based drug design (vFBDD) platform was utilized to identify novel non-aromatic fragments which make productive hydrogen bond interactions with Arg 70 on the αC-helix. Molecules incorporating these fragments were found to be potent inhibitors of p38 kinase. X-ray co-crystal structures confirmed the predicted binding modes. A lead compound was identified as a potent (p38α IC(50)=22 nM) and highly selective (≥ 150-fold against 150 kinase panel) DFG-out p38 kinase inhibitor.
Subject(s)
Computer Simulation , Drug Discovery , Enzyme Inhibitors , Oligopeptides/chemistry , Thiophenes , p38 Mitogen-Activated Protein Kinases/antagonists & inhibitors , Adenosine Triphosphate/chemistry , Animals , Crystallography, X-Ray , Dexamethasone/pharmacology , Enzyme Activation/drug effects , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Humans , Inhibitory Concentration 50 , Mice , Models, Molecular , Molecular Structure , Rats , Thiophenes/chemical synthesis , Thiophenes/chemistry , Thiophenes/pharmacologyABSTRACT
The synthesis and optimization of a series of orally bioavailable 1-(1H-indol-4-yl)-3,5-disubstituted benzene analogues as antimitotic agents are described. A functionalized dibromobenzene intermediate was used as a key scaffold, which when modified by sequential Suzuki coupling and Buchwald-Hartwig amination provided a flexible entry to 1,3,5-trisubstituted phenyl compounds. A 1H-indol-4-yl moiety at the 1-position was determined to be a critical feature for optimal potency. The compounds have been shown to induce cell cycle arrest at the G2/M phase and demonstrate efficacy in both cell viability and cell proliferation assays. The primary site of action for these agents is revealed by their colchicine competitive inhibition of tubulin polymerization, and a computational model has been developed for the association of these compounds to tubulin. An optimized lead LP-261 significantly inhibits growth of a human non-small-cell lung tumor (NCI-H522) in a mouse xenograft model.
Subject(s)
Indoles/chemical synthesis , Isonicotinic Acids/chemical synthesis , Sulfonamides/chemical synthesis , Tubulin Modulators/chemical synthesis , Animals , Biological Availability , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Colchicine/chemistry , Drug Screening Assays, Antitumor , G2 Phase , Humans , Indoles/chemistry , Indoles/pharmacology , Isonicotinic Acids/chemistry , Isonicotinic Acids/pharmacology , Mice , Mice, Nude , Models, Molecular , Neoplasm Transplantation , Rats , Rats, Sprague-Dawley , Structure-Activity Relationship , Sulfonamides/chemistry , Sulfonamides/pharmacology , Transplantation, Heterologous , Tubulin/chemistry , Tubulin Modulators/chemistry , Tubulin Modulators/pharmacologyABSTRACT
Two new classes of diphenylether inhibitors of p38alpha MAP kinase are described. Both chemical classes are based on a common diphenylether core that is identified by simulated fragment annealing as one of the most favored chemotypes within a prominent hydrophobic pocket of the p38alpha ATP-binding site. In the fully elaborated molecules, the diphenylether moiety acts as an anchor occupying the deep pocket, while polar extensions make specific interactions with either the adenine binding site or the phosphate binding site of ATP. The synthesis, crystallographic analysis, and biological activity of these p38alpha inhibitors are discussed.
Subject(s)
Biphenyl Compounds/chemistry , Biphenyl Compounds/pharmacology , Ethers/chemistry , Ethers/pharmacology , Mitogen-Activated Protein Kinase 14/antagonists & inhibitors , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Crystallography, X-Ray , Humans , Models, Molecular , Molecular Structure , Protein Binding , Protein Kinase Inhibitors/classification , Structure-Activity RelationshipABSTRACT
Heterocyclic demonstration libraries for agrochemical screening were prepared from the common intermediates 2-methoxy-6-oxo-1,4,5,6-tetrahydropyridine-3-carbonitriles (1), using standard solution-phase techniques. A total of 18 screening libraries were prepared in good to excellent yields. Several members of these libraries were active in the first level of agrochemical screening, especially in the fungicide screen.