ABSTRACT
Heat-shock protein-90 is an attractive target for anticancer drugs, as heat-shock protein-90 blockers such as the ansamycin 17-(allylamino)-17-demethoxygeldanamycin greatly reduce the expression of many signaling molecules that are disregulated in cancer cells and are key drivers of tumor growth and metastasis. While 17-(allylamino)-17-demethoxygeldanamycin has shown promise in clinical trials, this compound class has significant template-related drawbacks. In this paper, we describe a new, potent non-ansamycin small-molecule inhibitor of heat-shock protein-90, BX-2819, containing resorcinol and triazolothione rings. Structural studies demonstrate binding of BX-2819 to the ADP/ATP-binding pocket of heat-shock protein-90. The compound blocked expression of heat-shock protein-90 client proteins in cancer cell lines and inhibited cell growth with a potency similar to 17-(allylamino)-17-demethoxygeldanamycin. In a panel of four cancer cell lines, BX-2819 blocked growth with an average IC(50) value of 32 nM (range of 7-72 nM). Efficacy studies demonstrated that treatment with BX-2819 significantly inhibited the growth of NCI-N87 and HT-29 tumors in nude mice, consistent with pharmacodynamic studies showing inhibition of heat-shock protein-90 client protein expression in tumors for greater than 16 h after dosing. These data support further studies to assess the potential of BX-2819 and related analogs for the treatment of cancer.
Subject(s)
HSP90 Heat-Shock Proteins/antagonists & inhibitors , Triazoles/pharmacology , Animals , Benzoquinones/chemistry , Benzoquinones/pharmacology , Cell Line, Tumor , Computer Simulation , Crystallography, X-Ray , Drug Screening Assays, Antitumor , HSP90 Heat-Shock Proteins/metabolism , HT29 Cells , Humans , Lactams, Macrocyclic/chemistry , Lactams, Macrocyclic/pharmacology , Mice , Mice, Nude , Transplantation, Heterologous , Triazoles/chemistry , Xenograft Model Antitumor AssaysABSTRACT
Based on the lead compound BX-517, a series of C-4' substituted indolinones have been synthesized and evaluated for PDK1 inhibition. Modification at C-4' of the pyrrole afforded potent compounds (7b and 7d) with improved solubility and ADME properties. In this letter, we describe the synthesis, selectivity profile, and pharmacokinetic data of selected compounds.
Subject(s)
Indoles/chemistry , Protein Kinase Inhibitors/pharmacology , Protein Serine-Threonine Kinases/antagonists & inhibitors , Urea/analogs & derivatives , 3-Phosphoinositide-Dependent Protein Kinases , Cell Line, Tumor , Humans , Indoles/pharmacology , Protein Kinase Inhibitors/chemistry , Urea/chemistry , Urea/pharmacologyABSTRACT
There remains a high unmet medical need for a safe oral therapy for thrombotic disorders. The serine protease factor Xa (fXa), with its central role in the coagulation cascade, is among the more promising targets for anticoagulant therapy and has been the subject of intensive drug discovery efforts. Investigation of a hit from high-throughput screening identified a series of thiophene-substituted anthranilamides as potent nonamidine fXa inhibitors. Lead optimization by incorporation of hydrophilic groups led to the discovery of compounds with picomolar inhibitory potency and micromolar in vitro anticoagulant activity. Based on their high potency, selectivity, oral pharmacokinetics, and efficacy in a rat venous stasis model of thrombosis, compounds ZK 814048 (10b), ZK 810388 (13a), and ZK 813039 (17m) were advanced into development.
Subject(s)
Amides/chemical synthesis , Aminopyridines/chemical synthesis , Anticoagulants/chemical synthesis , Factor Xa Inhibitors , Thiophenes/chemical synthesis , ortho-Aminobenzoates/chemical synthesis , Amides/pharmacokinetics , Amides/pharmacology , Aminopyridines/pharmacokinetics , Aminopyridines/pharmacology , Animals , Anticoagulants/pharmacokinetics , Anticoagulants/pharmacology , Crystallography, X-Ray , Dogs , Humans , In Vitro Techniques , Male , Models, Molecular , Prothrombin Time , Rats , Rats, Wistar , Structure-Activity Relationship , Thiophenes/pharmacokinetics , Thiophenes/pharmacology , Venous Thrombosis/drug therapy , ortho-Aminobenzoates/pharmacokinetics , ortho-Aminobenzoates/pharmacologyABSTRACT
HTS screening identified 1 with micromolar inhibitory activity against PDK1. Optimization of 1 afforded 4i (BX-517) which has single-digit nanomolar activity against PDK1 and excellent selectivity against PKA.
Subject(s)
Indoles/chemistry , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Protein Serine-Threonine Kinases/antagonists & inhibitors , 3-Phosphoinositide-Dependent Protein Kinases , Drug Design , Models, Molecular , Molecular Structure , Protein Kinase Inhibitors/chemical synthesisABSTRACT
High throughput screening (HTS) led to the identification of the guanylhydrazone of 2-(4-chlorobenzyloxy)-5-bromobenzaldehyde as a CCR5 receptor antagonist. Initial modifications of the guanylhydrazone series indicated that substitution of the benzyl group at the para-position was well tolerated. Substitution at the 5-position of the central phenyl ring was critical for potency. Replacement of the guanylhydrazone group led to the discovery of a novel series of CCR5 antagonists.
Subject(s)
Anti-HIV Agents/chemistry , Anti-Inflammatory Agents, Non-Steroidal/chemistry , CCR5 Receptor Antagonists , Mitoguazone/analogs & derivatives , Anti-HIV Agents/chemical synthesis , Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Cells, Cultured , Drug Evaluation, Preclinical , Humans , Inhibitory Concentration 50 , Structure-Activity RelationshipABSTRACT
The activated Factor VII/tissue factor complex (FVIIa/TF) plays a key role in the formation of blood clots. Inhibition of this complex may lead to new antithrombotic drugs. An X-ray crystal structure of a fluoropyridine-based FVIIa/TF inhibitor bound in the active site of the enzyme complex suggested that incorporation of substitution at the 5-position of the hydroxybenzoic acid side chain could lead to the formation of more potent inhibitors through interactions with the S1'/S2' pocket.
Subject(s)
Enzyme Inhibitors/chemical synthesis , Factor VIIa/chemistry , Fibrinolytic Agents/chemical synthesis , Pyridines/chemical synthesis , Thromboplastin/chemistry , Binding Sites , Crystallography, X-Ray , Enzyme Inhibitors/chemistry , Factor VIIa/antagonists & inhibitors , Factor Xa Inhibitors , Fibrinolytic Agents/chemistry , Fibrinolytic Agents/pharmacology , Humans , Inhibitory Concentration 50 , Protein Binding , Prothrombin Time , Pyridines/chemistry , Structure-Activity Relationship , Thromboplastin/antagonists & inhibitorsABSTRACT
The phosphoinositide 3-kinase/3-phosphoinositide-dependent kinase 1 (PDK1)/Akt signaling pathway plays a key role in cancer cell growth, survival, and tumor angiogenesis and represents a promising target for anticancer drugs. Here, we describe three potent PDK1 inhibitors, BX-795, BX-912, and BX-320 (IC(50) = 11-30 nm) and their initial biological characterization. The inhibitors blocked PDK1/Akt signaling in tumor cells and inhibited the anchorage-dependent growth of a variety of tumor cell lines in culture or induced apoptosis. A number of cancer cell lines with elevated Akt activity were >30-fold more sensitive to growth inhibition by PDK1 inhibitors in soft agar than on tissue culture plastic, consistent with the cell survival function of the PDK1/Akt signaling pathway, which is particularly important for unattached cells. BX-320 inhibited the growth of LOX melanoma tumors in the lungs of nude mice after injection of tumor cells into the tail vein. The effect of BX-320 on cancer cell growth in vitro and in vivo indicates that PDK1 inhibitors may have clinical utility as anticancer agents.
