ABSTRACT
Pyridyl aminothiazoles comprise a novel class of ATP-competitive Chk1 inhibitors with excellent inhibitory potential. Modification of the core with ethylenediamine amides provides compounds with low picomolar potency and very high residence times. Investigation of binding parameters of such compounds using X-ray crystallography and molecular dynamics simulations revealed multiple hydrogen bonds to the enzyme backbone as well as stabilization of the conserved water molecules network in the hydrophobic binding region.
Subject(s)
Antineoplastic Agents/chemical synthesis , Protein Kinase Inhibitors/chemical synthesis , Protein Kinases/chemistry , Pyridines/chemical synthesis , Thiazoles/chemical synthesis , Amides/chemistry , Antineoplastic Agents/pharmacology , Binding Sites , Checkpoint Kinase 1 , Crystallography, X-Ray , Drug Design , Ethylenediamines/chemistry , Humans , Hydrogen Bonding , Kinetics , Molecular Dynamics Simulation , Molecular Structure , Protein Binding , Protein Kinase Inhibitors/pharmacology , Protein Kinases/metabolism , Pyridines/pharmacology , Structure-Activity Relationship , Thiazoles/pharmacology , Water/chemistryABSTRACT
Translation of significant biochemical activity of pyridyl aminothiazole class of Chk1 inhibitors into functional CEA potency required analysis and adjustment of both physical properties and kinase selectivity profile of the series. The steps toward optimization of cellular potency included elimination of CDK7 activity, reduction of molecular weight and polar surface area and increase in lipophilicity of the molecules in the series.
Subject(s)
Antineoplastic Agents/chemical synthesis , Protein Kinase Inhibitors/chemical synthesis , Protein Kinases/chemistry , Pyridines/chemical synthesis , Thiazoles/chemical synthesis , Antineoplastic Agents/pharmacology , Cell Cycle Checkpoints/drug effects , Cell Line, Tumor , Cell Membrane Permeability , Checkpoint Kinase 1 , Cyclin-Dependent Kinases/antagonists & inhibitors , Cyclin-Dependent Kinases/chemistry , Drug Design , Halogenation , Humans , Kinetics , Molecular Structure , Protein Kinase Inhibitors/pharmacology , Protein Kinases/metabolism , Pyridines/pharmacology , Structure-Activity Relationship , Thiazoles/pharmacology , Cyclin-Dependent Kinase-Activating KinaseABSTRACT
The type 1 insulin-like growth factor receptor (IGF-1R) is often overexpressed on tumor cells and is believed to play an important role in anchorage-independent proliferation. Additionally, cell culture studies have indicated that IGF-1R confers increased resistance to apoptosis caused by radiation or chemotherapeutic agents. Thus, inhibitors of the intracellular kinase domain of this receptor may have utility for the clinical treatment of cancer. As part of an effort to develop clinically useful inhibitors of IGF-1R kinase, a novel class of pyrrole-5-carboxaldehyde compounds was investigated. The compounds exhibited selectivity against the closely related insulin receptor kinase intrinsically and in cell-based assays. The inhibitors formed a reversible, covalent adduct at the kinase active site, and treatment of such adducts with sodium borohydride irreversibly inactivated the enzyme. Analysis of a tryptic digest of a covalently modified IGF-1R kinase fragment revealed that the active site Lys1003 had been reductively alkylated with the aldehyde inhibitor. Reductive alkylation of the insulin receptor kinase with one of these inhibitors led to a similarly inactivated enzyme which was examined by X-ray crystallography. The crystal structure confirmed the modification of the active site lysine side chain and revealed details of the key interactions between the inhibitor and enzyme.