ABSTRACT
The hedgehog (Hh) pathway is a developmental signaling pathway that is essential to the proper embryonic development of many vertebrate systems. Dysregulation of Hh signaling has been implicated as a causative factor in the development and progression of several forms of human cancer. As such, the development of small molecule inhibitors of Hh signaling as potential anti-cancer chemotherapeutics has been a major area of research interest in both academics and industry over the past ten years. Through these efforts, synthetic small molecules that target multiple components of the Hh pathway have been identified and advanced to preclinical or clinical development. The goal of this review is to provide an update on the current status of several synthetic small molecule Hh pathway inhibitors and explore the potential of several recently disclosed inhibitory scaffolds.
Subject(s)
Antineoplastic Agents/pharmacology , Neoplasms/drug therapy , Neoplasms/metabolism , Protein Serine-Threonine Kinases/antagonists & inhibitors , Signal Transduction/drug effects , Small Molecule Libraries/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Hippo Signaling Pathway , Humans , Molecular Structure , Protein Serine-Threonine Kinases/metabolism , Small Molecule Libraries/chemical synthesis , Small Molecule Libraries/chemistryABSTRACT
High concentrations (30 microM-5 mM) of the neutral amino acids L-serine, L-cysteine, L-alanine, L-proline and glycine elicited inward current responses when applied to hippocampal neurons patch clamped at -60 mV in the presence of 1-10 microM glycine and 1 microM strychnine. The amplitude of the response to L-serine increased in a concentration-dependent fashion within the range 0.1-10 mM (EC50, 2.6 mM). L-Serine (1 mM) currents were attenuated by Mg2+ (100 microM) and completely blocked by the competitive N-methyl-D-aspartate (NMDA) antagonist 3-(2-carboxypiperazin-4-yl)-propyl-1- phosphonic acid (CPP) (30 microM). The CPP block could be overcome by raising the concentration of L-serine. We conclude that high concentrations of some neutral amino acids activate NMDA receptor-coupled ion channels by acting as agonists at the NMDA recognition site.
Subject(s)
Amino Acids/pharmacology , Hippocampus/cytology , Neurons/metabolism , Receptors, N-Methyl-D-Aspartate/drug effects , Animals , Female , Hippocampus/drug effects , Magnesium/pharmacology , Membrane Potentials/drug effects , Neurons/drug effects , Piperazines/pharmacology , Pregnancy , Rats , Rats, Inbred Strains , Receptors, Amino Acid , Receptors, Cell Surface/drug effects , Receptors, Cell Surface/metabolism , Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors , Serine/pharmacologyABSTRACT
The potentiation of gamma-aminobutyric acid (GABA) receptor-mediated 36Cl- uptake by various steroids has been characterized in rat cerebral cortical synaptoneurosomes. Several of these steroids, including 3 alpha-hydroxy-5 alpha-pregnan-20-one (3 alpha-OH-DHP) and 3 alpha,21-dihydroxy-5 alpha-pregnan-20-one (THDOC), increase the potency of muscimol to stimulate 36Cl- uptake in a concentration-dependent and stereospecific manner. Concentration-response curves for 3 alpha-OH-DHP, THDOC, 3 alpha-hydroxy-pregn-4-en-20-one, and pentobarbital enhancement of muscimol-stimulated 36Cl- uptake are biphasic, with Hill coefficients significantly less than 1.0. Computer-modeling (ALLFIT analysis) of these curves suggests that these steroids and pentobarbital interact with multiple binding sites on GABAA receptor(s). In contrast, the concentration-response curve for THDOC 21-mesylate is monophasic, with a smaller maximal response, and yields a Hill coefficients of 1.0. In addition to modulating GABA receptor-mediated 36Cl- uptake, THDOC enhanced the ability of the benzodiazepine clonazepam to potentiate muscimol-stimulated 36Cl- uptake. The central benzodiazepine antagonist Ro15-1788 failed to inhibit THDOC-induced potentiation of muscimol-stimulated 36Cl- uptake, although it has been previously reported to inhibit some of the behavioral actions of THDOC. In contrast to the A ring-reduced metabolites and analogues of progesterone and deoxycorticosterone, glucocorticoids had no effect on muscimol-stimulated 36Cl- uptake in cerebral cortical synaptoneurosomes at concentrations between 20 nM and 5 microM.
Subject(s)
Chlorides/metabolism , Ion Channels/drug effects , Membrane Proteins/metabolism , Receptors, GABA-A/drug effects , Steroids/pharmacology , 20-alpha-Dihydroprogesterone/analogs & derivatives , 20-alpha-Dihydroprogesterone/pharmacology , Animals , Cerebral Cortex/drug effects , Chloride Channels , Desoxycorticosterone/analogs & derivatives , Desoxycorticosterone/pharmacology , In Vitro Techniques , Ion Channel Gating/drug effects , Pregnanolone/pharmacology , Rats , Receptors, GABA-A/metabolism , Steroids/metabolism , Structure-Activity Relationship , Synaptosomes/drug effectsABSTRACT
Cell killing by human immunodeficiency virus (HIV) is thought to contribute to many of the defects of the acquired immunodeficiency syndrome (AIDS). Two types of cytopathology are observed in HIV-infected cultured cells: cell-cell fusion and killing of single cells. Both killing processes appear to involve cell surface effects of HIV. A model is proposed for the HIV-mediated cell surface processes which could result in cell-cell fusion and single cell killing. The purpose of this model is to define the potential roles of individual viral envelope and cell surface molecules in cell killing processes and to identify alternative routes to the establishment of persistently-infected cells. Elucidation of HIV-induced cell surface effects may provide the basis for a rational approach to the design of antiviral agents which are selective for HIV-infected cells.
