ABSTRACT
Histone H3 lysine 79 (H3K79) methyltransferase DOT1L plays an important role in the activation and maintenance of gene transcription; it is also essential for maintenance of embryonic development, as well as the normal function of hematopoietic system, heart and kidney. However, the over expression of DOT1L is associated with the occurring and progress of numerous malignant tumors, so more and more attention has been paid to DOT1L. Therefore, it is of great significance to study and develop inhibitors of DOT1L. The inhibitors could serve as a tool in the investigation of the biological function, and have the potential to be developed into novel anti-cancer agents in the anticancer therapy. This paper mainly describes the structure and function of DOT1L, the relationship between DOT1L and tumors as well as the latest research progress of DOT1L inhibitors; with expect to provide some useful references for the subsequent research.
ABSTRACT
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)
Animals , Female , Humans , Antineoplastic Agents , Therapeutic Uses , Benzimidazoles , Therapeutic Uses , Breast Neoplasms , Drug Therapy , Genetics , DNA Repair , Drug Therapy, Combination , Enzyme Inhibitors , Therapeutic Uses , Indoles , Therapeutic Uses , Melanoma , Drug Therapy , Mutation , Ovarian Neoplasms , Drug Therapy , Genetics , Phthalazines , Therapeutic Uses , Piperazines , Therapeutic Uses , Poly(ADP-ribose) Polymerase InhibitorsABSTRACT
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)
Humans , Antineoplastic Agents , Therapeutic Uses , Clinical Trials, Phase III as Topic , Drug Delivery Systems , Methods , Neoplasms , Drug Therapy , Protein Kinase Inhibitors , Therapeutic Uses , Signal TransductionABSTRACT
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.