ABSTRACT
Inhibition of mitotic kinesins represents a novel approach for the discovery of a new generation of anti-mitotic cancer chemotherapeutics. We report here the discovery of the first potent and selective inhibitor of centromere-associated protein E (CENP-E) 3-chloro-N-{(1S)-2-[(N,N-dimethylglycyl)amino]-1-[(4-{8-[(1S)-1-hydroxyethyl]imidazo[1,2-a]pyridin-2-yl}phenyl)methyl]ethyl}-4-[(1-methylethyl)oxy]benzamide (GSK923295; 1), starting from a high-throughput screening hit, 3-chloro-4-isopropoxybenzoic acid 2. Compound 1 has demonstrated broad antitumor activity in vivo and is currently in human clinical trials.
ABSTRACT
Modification of the benzo rings of 3-(1,1-dioxo-2H-(1,2,4)-benzothiadiazin-3-yl)-4-hydroxy-2(1H)-quinolinones into heteroaromatic systems was investigated to enhance physicochemical properties and potency profile of this class of inhibitors. The synthesis and biological activity of the derived compounds is discussed.
Subject(s)
Chemistry, Pharmaceutical/methods , Quinolones/chemical synthesis , Viral Nonstructural Proteins/antagonists & inhibitors , Antiviral Agents/chemical synthesis , Antiviral Agents/pharmacology , Drug Design , Genotype , Hepacivirus/metabolism , Humans , Inhibitory Concentration 50 , Models, Chemical , Molecular Structure , Protein Binding , Quinolones/pharmacology , Structure-Activity RelationshipABSTRACT
The synthesis and optimisation of HCV NS5B polymerase inhibitors with improved potency versus the existing compound 1 is described. Substitution in the benzothiadiazine portion of the molecule, furnishing improvement in potency in the high protein Replicon assay, is highlighted, culminating in the discovery of 12h, a highly potent oxyacetamide derivative.
Subject(s)
Antiviral Agents/chemical synthesis , Benzothiadiazines/chemistry , Chemistry, Pharmaceutical/methods , Hepacivirus/enzymology , Viral Nonstructural Proteins/antagonists & inhibitors , Administration, Oral , Animals , Antiviral Agents/pharmacology , Benzothiadiazines/pharmacology , Drug Design , Humans , Inhibitory Concentration 50 , Models, Chemical , Molecular Conformation , Molecular Structure , Rats , Structure-Activity RelationshipABSTRACT
Kinesin spindle protein (KSP), an ATPase responsible for spindle pole separation during mitosis that is present only in proliferating cells, has become a novel and attractive anticancer target with potential for reduced side effects compared to currently available therapies. We report herein the discovery of the first known ATP-competitive inhibitors of KSP, which display a unique activity profile as compared to the known loop 5 (L5) allosteric KSP inhibitors that are currently under clinical evaluation. Optimization of this series led to the identification of biphenyl sulfamide 20, a potent KSP inhibitor with in vitro antiproliferative activity against human cells with either wild-type KSP (HCT116) or mutant KSP (HCT116 D130V). In a murine xenograft model with HCT116 D130V tumors, 20 showed significant antitumor activity following intraperitoneal dosing, providing in vivo proof-of-principle of the efficacy of an ATP-competitive KSP inhibitor versus tumors that are resistant to the other known KSP inhibitors.
Subject(s)
Adenosine Triphosphate/metabolism , Antineoplastic Agents/chemical synthesis , Biphenyl Compounds/chemical synthesis , Kinesins/antagonists & inhibitors , Sulfonamides/chemical synthesis , Animals , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/pharmacology , Biphenyl Compounds/pharmacokinetics , Biphenyl Compounds/pharmacology , Cell Line, Tumor , Cell Proliferation/drug effects , Drug Screening Assays, Antitumor , Female , Humans , Kinesins/genetics , Mice , Mice, Nude , Mutation , Neoplasm Transplantation , Structure-Activity Relationship , Sulfonamides/pharmacokinetics , Sulfonamides/pharmacologyABSTRACT
Recently, we disclosed a new class of HCV polymerase inhibitors discovered through high-throughput screening (HTS) of the GlaxoSmithKline proprietary compound collection. This interesting class of 3-(1,1-dioxo-2H-1,2,4-benzothiadiazin-3-yl)-4-hydroxy-2(1H)-quinolinones potently inhibits HCV polymerase enzymatic activity and inhibits the ability of the subgenomic HCV replicon to replicate in Huh-7 cells. This report will focus on the structure-activity relationships (SAR) of substituents on the quinolinone ring, culminating in the discovery of 1-(2-cyclopropylethyl)-3-(1,1-dioxo-2H-1,2,4-benzothiadiazin-3-yl)-6-fluoro-4-hydroxy-2(1H)-quinolinone (130), an inhibitor with excellent potency in biochemical and cellular assays possessing attractive molecular properties for advancement as a clinical candidate. The potential for development and safety assessment profile of compound 130 will also be discussed.
