laq824 and Neoplasms

The indole scaffold is one of the most widespread heterocycles in the naturally occurring and synthetic bioactive compounds including anticancer agents. Due to its biodiversity and versatility, it has been a highly privileged motif for the target-based design and development of anticancer agents. In the last decade, many researchers have reported various indole-based compounds with distinct mechanisms involved in producing potential anticancer activities, indicating the importance of indole motif in the anticancer drug development. The present article aims to review the current application of indole core in the design of new anticancer agents that may act via various targets such as histone deacetylases (HDACs), sirtuins, PIM kinases, DNA topoisomerases and σ receptors. Targeting these enzymes or receptors in cancer cells by indole-derived compounds can be a powerful tool for the management of cancer.

Topics: Antineoplastic Agents; Dose-Response Relationship, Drug; Drug Design; Humans; Indoles; Molecular Structure; Neoplasms; Structure-Activity Relationship

Indoles constitute extensively explored heterocyclic ring systems with wide range of applications in pathophysiological conditions that is, cancer, microbial and viral infections, inflammation, depression, migraine, emesis, hypertension, etc. Presence of indole nucleus in amino acid tryptophan makes it prominent in phytoconstituents such as perfumes, neurotransmitters, auxins (plant hormones), indole alkaloids etc. The interesting molecular architecture of indole makes them suitable candidates for the drug development. This review article provides an overview of the chemistry, biology, and toxicology of indoles focusing on their application as drugs. Our effort is to corroborate the information available on the natural indole alkaloids, indole based FDA approved drugs and clinical trial candidates having diverse therapeutic implementations. This compiled information may serve as a benchmark for the alteration of existing ligands to design novel potent molecules with lesser side effects.

Topics: Animals; Anti-Infective Agents; Anti-Inflammatory Agents; Antiemetics; Antineoplastic Agents; Bacterial Infections; Chemistry, Pharmaceutical; Cholinergic Antagonists; Drug Discovery; Humans; Indoles; Migraine Disorders; Mycoses; Neoplasms; Virus Diseases

It has been shown that epigenetic modifications play an important role in tumorigenesis. Thus, affecting epigenetic tumorigenic alterations can represent a promising strategy for anticancer targeted therapy. Among the key chromatin modifying enzymes which influence gene expression, histone acetyltransferases (HATs) and histone deacetylases (HDACs) have recently attracted interest because of their impact on tumor development and progression. Increased expression of HDACs and disrupted activities of HATs have been found in several tumor types, with a consequent hypoacetylated state of chromatin that can be strictly correlated with low expression of either tumor suppressor or pro-apoptotic genes. Histone deacetylase inhibitors (HDACIs) represent a new and promising class of antitumor drugs that influence gene expression by enhancing acetylation of histones in specific chromatin domains. HDACIs have been shown to exert potent anticancer activities inducing cell cycle arrest and apoptosis. Notably, a high efficacy of these drugs has been selectively revealed in malignant cells rather than in normal cells. Moreover, the therapeutic potential of these agents is also supported by the evidence that HDACIs downregulate genes involved in tumor progression, invasion and angiogenesis. Several HDACIs are currently under clinical investigation, including vorinostat (SAHA), romidepsin (depsipeptide, FK-228), LAQ824/LBH589 and belinostat (PXD101), compounds that have shown therapeutic potential in many types of malignancies including solid tumors. Based on the ability of HDACIs to regulate many signaling pathways, co-treatment of these compounds with molecular targeted drugs is a promising strategy against many types of tumors.

Topics: Antineoplastic Agents; Apoptosis; Chromatin; Depsipeptides; Epigenesis, Genetic; Gene Expression Regulation, Neoplastic; Histone Deacetylase Inhibitors; Humans; Hydroxamic Acids; Models, Biological; Models, Chemical; Neoplasms; Protein Structure, Tertiary; Sulfonamides; Vorinostat

To determine the safety, maximum tolerated dose, and pharmacokinetic-pharmacodynamic profile of a histone deacetylase inhibitor, LAQ824, in patients with advanced malignancy.. LAQ824 was administered i.v. as a 3-h infusion on days 1, 2, and 3 every 21 days. Western blot assays of peripheral blood mononuclear cell lysates and tumor biopsies pretherapy and posttherapy evaluated target inhibition and effects on heat shock protein-90 (HSP90) client proteins and HSP72.. Thirty-nine patients (22 male; median age, 53 years; median Eastern Cooperative Oncology Group performance status 1) were treated at seven dose levels (mg/m(2)): 6 (3 patients), 12 (4 patients), 24 (4 patients), 36 (4 patients), 48 (4 patients), 72 (19 patients), and 100 (1 patient). Dose-escalation used a modified continual reassessment method. Dose-limiting toxicities were transaminitis, fatigue, atrial fibrillation, raised serum creatinine, and hyperbilirubinemia. A patient with pancreatic cancer treated at 100 mg/m(2) died on course one at day 18 with grade 3 hyperbilirubinemia and neutropenia, fever, and acute renal failure. The area under the plasma concentration curve increased proportionally with increasing dose; median terminal half-life ranged from 8 to 14 hours. Peripheral blood mononuclear cell lysates showed consistent accumulation of acetylated histones posttherapy from 24 mg/m(2); higher doses resulted in increased and longer duration of pharmacodynamic effect. Changes in HSP90 client protein and HSP72 levels consistent with HSP90 inhibition were observed at higher doses. No objective response was documented; 3 patients had stable disease lasting up to 14 months. Based on these data, future efficacy trials should evaluate doses ranging from 24 to 72 mg/m(2).. LAQ824 was well tolerated at doses that induced accumulation of histone acetylation, with higher doses inducing changes consistent with HSP90 inhibition.

Topics: Acetylation; Adult; Aged; Blotting, Western; Cohort Studies; Disease Progression; Enzyme Inhibitors; Female; Histone Deacetylase Inhibitors; Histone Deacetylases; Histones; HSP90 Heat-Shock Proteins; Humans; Hydroxamic Acids; Male; Maximum Tolerated Dose; Middle Aged; Neoplasms; Prognosis; Survival Rate

Modification of the cap group of biphenylacrylohydroxamic acid-based HDAC inhibitors led to the identification of a new derivative (3) characterized by an indolyl-substituted 4-phenylcinnamic skeleton. Molecular docking was used to predict the optimal conformation in the class I HDACs active site. Compound 3 showed HDAC inhibitory activity and antiproliferative activity against a panel of tumor cell lines, in the low μM range. The compound was further tested in vitro for acetylation of histone H4 and other non-histone proteins, and in vivo in a colon carcinoma model, showing significant proapoptotic and antitumor activities.

Topics: Antineoplastic Agents; Apoptosis; Biphenyl Compounds; Colonic Neoplasms; Drug Screening Assays, Antitumor; HCT116 Cells; Histone Deacetylase Inhibitors; Histone Deacetylases; Humans; Hydroxamic Acids; Molecular Docking Simulation; Neoplasms; Structure-Activity Relationship

Previously, we reported a click-chemistry based approach to the synthesis of a novel class of histone deacetylase (HDAC) inhibitors [1]. The lead compound NSC746457 was found to be as potent as SAHA (Vorinostat). Further optimization of NSC746457 by using the HDAC2-TSA crystal structure is described herein. Docking of NSC746457 into HDAC2 binding domain suggested that the hydrophobic residue Phe210 flanking the cap-group binding-motif could be exploited for structural optimization. Substitution on the methylene group of cinnamic cap region led to identification of more potent HDAC inhibitors: isopropyl derivative 5 and tert-butyl derivative 6, with an IC(50) value of 22 nM and 18 nM, respectively.

Topics: Antineoplastic Agents; Binding Sites; Cell Line, Tumor; Cell Proliferation; Click Chemistry; Crystallography, X-Ray; Drug Design; Drug Screening Assays, Antitumor; Histone Deacetylase 1; Histone Deacetylase 2; Histone Deacetylase Inhibitors; Humans; Hydrophobic and Hydrophilic Interactions; Hydroxamic Acids; Models, Molecular; Neoplasms; Phenylalanine; Protein Binding; Protein Structure, Secondary; Structure-Activity Relationship; Triazoles; Vorinostat