Subject(s)
Antibiotics, Antineoplastic/chemistry , Carboxylic Acids/chemistry , Cyclopentanes/chemistry , Streptomyces/chemistry , Antibiotics, Antineoplastic/isolation & purification , Antibiotics, Antineoplastic/pharmacology , Carboxylic Acids/isolation & purification , Carboxylic Acids/pharmacology , Cyclopentanes/isolation & purification , Cyclopentanes/pharmacology , HeLa Cells , HumansABSTRACT
A novel series of macrocyclic compounds were designed and synthesized as multi-target inhibitors targeting HDAC, FLT3 and JAK2. Some of these compounds exhibited potent HDAC inhibition as well as FLT3 and JAK2 inhibition under both cell-free and cellular conditions. In vitro antiproliferative assay indicated that these compounds were interestingly more cytotoxic to MV4-11 cells bearing FLT3-ITD mutation and HEL cells bearing JAK2(V617F) mutation.
Subject(s)
Antineoplastic Agents/pharmacology , Drug Design , Histone Deacetylases/chemistry , Janus Kinase 2/antagonists & inhibitors , Macrocyclic Compounds/chemical synthesis , Macrocyclic Compounds/pharmacology , fms-Like Tyrosine Kinase 3/antagonists & inhibitors , Antineoplastic Agents/chemical synthesis , Apoptosis/drug effects , Blotting, Western , Cell Proliferation/drug effects , HeLa Cells , Histone Deacetylase Inhibitors/chemical synthesis , Histone Deacetylase Inhibitors/pharmacology , Humans , Molecular Docking Simulation , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/pharmacology , Signal TransductionABSTRACT
The poly(ADP-ribose) polymerases (PARPs) is an important group of enzymes in DNA repair pathways, especially the base excision repair (BER) for DNA single-strand breaks (SSBs) repair. Inhibition of PARP in DNA repair-defective tumors (like those with BRAC1/2 mutations) can lead to cell death and genomic instability, what is so called "synthetic lethality". Currently, PARP inhibitors combined with cytotoxic chemotherapeutic agents in the treatment of BRCA-1/2 deficient cancers are in the clinical development. In this review, we will be focused on the development of combination application of PARP inhibitors with other anticancer agents in clinical trials.
Subject(s)
Antineoplastic Agents/therapeutic use , Breast Neoplasms/drug therapy , Enzyme Inhibitors/therapeutic use , Ovarian Neoplasms/drug therapy , Poly(ADP-ribose) Polymerase Inhibitors , Animals , Benzimidazoles/therapeutic use , Breast Neoplasms/genetics , DNA Repair , Drug Therapy, Combination , Female , Humans , Indoles/therapeutic use , Melanoma/drug therapy , Mutation , Ovarian Neoplasms/genetics , Phthalazines/therapeutic use , Piperazines/therapeutic useABSTRACT
Signal transduction in cells plays an important role in the process of cellular metabolism, segmentation, differentiation, biological behaviors and cell death. Direct and indirect involvement of kinases in tumor growth, metastasis and apoptosis make them the most promising targets for anticancer discovery. Most of the kinase inhibitors in clinical use or in late development stages are multi-target kinase inhibitors (MTKIs). These MTKIs are demonstrated to exert potent anti-tumor effects through several different pathways. This review presents in the view of a medicinal chemistry point, a brief account and analysis of transduction pathways of representative MTKIs in clinical use or in late development stages.
Subject(s)
Antineoplastic Agents/therapeutic use , Drug Delivery Systems/methods , Neoplasms/drug therapy , Protein Kinase Inhibitors/therapeutic use , Signal Transduction , Clinical Trials, Phase III as Topic , HumansABSTRACT
Among those enzymes that regulate gene expression, histone deacetylases (HDACs) play important roles in cell cycles. Extensive studies were carried out in the field of HDACs and the applications of HDAC inhibitors (HDACIs) as chemotherapeutic interventions for diverse diseases. HDACIs have moved from laboratories to clinic uses. Huge bodies of related research results were well documented and dispersed in literature. According to our understanding, HDACIs can be broadly classified as hydroxamic acids, cyclic tetrapeptides, short chain fatty acids, benzamides and electrophilic ketones. Herein, we are going to review the design and their structure-activity relationships of HDACIs and according to their structural catalogs.
