Abstract:
:The bi-aryl urea multi-kinase inhibitor Sorafenib (BAY 43-9006, Nexavar) was initially approved for the treatment of unresectable hepatocellular carcinoma and advanced renal cell carcinoma. Eleven years after its first description in PubMed, the therapeutic potential of Sorafenib has been evaluated in an increasing number of studies, mainly focused on solid tumors. More recently, the potential usefullness of Sorafenib has started to emerge also against hematological malignancies. At the molecular level, besides the RAF kinase pathway, which represents the first therapeutic target of Sorafenib, additional kinases, in particular the vascular endothelial growth factor receptor, have been identified as important targets of Sorafenib. A great interest for the potential use of Sorafenib against acute myeloid leukemia (AML) arose when it was demonstrated that a specific mutation of a kinase gene, called FMS-like tyrosin-kinase-3- internal tandem duplication (FLT-3-ITD) and occurring in more than 30% of AML, represents a molecular target of Sorafenib. However, recent phase I and II clinical studies showed that, in spite of its ability to suppress the activity of this mutated kinase, resistence to Sorafenib rapidly occurs in AML, suggesting that Sorafenib will be more effective in combined therapy than used as single drug. Another critical molecular target of Sorafenib is the anti-apoptotic protein Mcl-1. The ability of Sorafenib to rapidly shut-off Mcl-1 in virtually all the hematological malignancies investigated, including the B-chronic lymphocytic leukemia, represents a key element for its antileukemic activity as well as for therapeutic combinations based on Sorafenib. In this respect, it is of particular interest that many chemotherapeutic drugs or innovative anti-neoplastic compounds, such as recombinant TRAIL or inibitors of MDM2 protein, are either unable to down-regulate Mcl-1 or in some instances promote a paradoxical induction of Mcl-1. In this review, the growing evidences for the role of Mcl-1 in mediating the anti-leukemic activity of Sorafenib will be discussed in relationship with promising therapeutic perspectives.
journal_name
Curr Med Chemjournal_title
Current medicinal chemistryauthors
Zauli G,Voltan R,Tisato V,Secchiero Pdoi
10.2174/092986712803341548subject
Has Abstractpub_date
2012-01-01 00:00:00pages
4875-84issue
28eissn
0929-8673issn
1875-533Xpii
CMC-EPUB-20120817-5journal_volume
19pub_type
杂志文章,评审abstract:BACKGROUND:Smac mimetics (also known as IAP antagonist) are a new class of targeted drugs having a goal to suppress the IAPs, reestablishing the apoptotic pathways and inducing cancer cell death. Therefore, development of Smac mimetics was considered an attractive strategy for the development of new anticancer drugs. L...
journal_title:Current medicinal chemistry
pub_type: 杂志文章,评审
doi:10.2174/0929867325666180313112229
更新日期:2018-01-01 00:00:00
abstract::Since the beginning of the 20th century, important medicinal progress has led medical doctors to think that the end of devastating epidemics has arrived. In 1930, the discovery of sulfamides and penicillin opened a wide area of applications able to fight against bacterial infections. However, almost all antibiotics we...
journal_title:Current medicinal chemistry
pub_type: 杂志文章,评审
doi:10.2174/092986705774933470
更新日期:2005-01-01 00:00:00
abstract::Chronic obstructive pulmonary disease (COPD) represents a heightened inflammatory response in the lung generally resulting from tobacco smoking-induced recruitment and activation of inflammatory cells and/or activation of lower airway structural cells. Several mediators can modulate activation and recruitment of these...
journal_title:Current medicinal chemistry
pub_type: 杂志文章
doi:10.2174/0929867327999200819145327
更新日期:2020-08-19 00:00:00
abstract::ATP binding cassette (ABC) transporters are involved in drug absorption, distribution and elimination. They also mediate multidrug resistance in cancer cells. Isoflavones, such as genistein (GNT), belong to a class of naturally-occurring compounds found at high concentrations in commonly consumed soya based-foods and ...
journal_title:Current medicinal chemistry
pub_type: 杂志文章,评审
doi:10.2174/0929867323666160406120711
更新日期:2016-01-01 00:00:00
abstract::The arachidonic acid metabolizing enzymes, cyclooxygenase-2 (COX-2) and 5- lipoxygenase (5-LOX), are both highly expressed during the carcinogenesis in colons. Cigarette smoking promotes these carcinogenic processes at the early stage during adenoma formation. In this article, the involvement of COX-2 and 5-LOX, along...
journal_title:Current medicinal chemistry
pub_type: 杂志文章,评审
doi:10.2174/0929867323666160321122431
更新日期:2016-01-01 00:00:00
abstract::Glucagon-like peptide-1 (GLP-1) is an insulinotropic hormone secreted from endocrine cells in the gut mucosa in response to meal ingestion. It is an important incretin hormone; mice with a null mutation in the GLP-1 receptor gene develop glucose intolerance. In addition, it inhibits gastrointestinal secretion and moti...
journal_title:Current medicinal chemistry
pub_type: 杂志文章,评审
doi:
更新日期:1999-11-01 00:00:00
abstract:BACKGROUND:Since the serendipitous discovery of the antitumor activity of cisplatin there has been a continuous surge in studies aimed at the development of new cytotoxic metal complexes. While the majority of these complexes have been designed to interact with nuclear DNA, other targets for anticancer metallodrugs att...
journal_title:Current medicinal chemistry
pub_type: 杂志文章,评审
doi:10.2174/0929867325666180307112029
更新日期:2019-01-01 00:00:00
abstract:BACKGROUND:Since Signal Transducer and Activator of Transcription 3 (STAT3) is a transcription factor which plays an important role in multiple aspects of cancer, including progression and migration, and it is constitutively activated in various human tumors, STAT3 inhibition has emerged as a validated strategy for the...
journal_title:Current medicinal chemistry
pub_type: 杂志文章,评审
doi:10.2174/0929867325666180719122729
更新日期:2019-01-01 00:00:00
abstract::Iron is a key element for every single living process. On a fundamental level, targeting iron is a valuable approach for the treatment of disorders caused by iron overload. Utilizing iron chelators as therapeutic agents has received expanding consideration in chelation therapy. Approved low molecular weight (MW) iron ...
journal_title:Current medicinal chemistry
pub_type: 杂志文章
doi:10.2174/0929867325666180904104318
更新日期:2019-01-01 00:00:00
abstract::Advances in combinatorial chemistry, high-throughput screening, and molecular modeling have revolutionized the process of drug discovery in the pharmaceutical industry. Drug discovery efforts for the primary protozoal parasitic diseases of the developing world, malaria, leishmaniasis, and trypanosomiasis, have also be...
journal_title:Current medicinal chemistry
pub_type: 杂志文章,评审
doi:10.2174/0929867003374615
更新日期:2000-08-01 00:00:00
abstract::Tetracyclines (TCs) and their non-antimicrobial analogs (CMTs) have therapeutic potential to inhibit tissue destructive disease processes, such as cancer invasion and metastasis, by inhibiting certain matrix metalloproteinases. Enhanced matrix metalloproteinase-2 (MMP-2; gelatinase A) activity has been correlated to c...
journal_title:Current medicinal chemistry
pub_type: 杂志文章
doi:10.2174/0929867013373660
更新日期:2001-02-01 00:00:00
abstract::Dendritic cells (DCs) are the most powerful antigen-presenting cells which link the innate and adaptive immune responses. Depending on the context DCs initiate the immune responses or contribute to immune tolerance. Any disturbance in their phenotypes and functions may initiate inflammatory or autoimmune diseases. Hen...
journal_title:Current medicinal chemistry
pub_type: 杂志文章
doi:10.2174/0929867327666200515101228
更新日期:2020-05-14 00:00:00
abstract::Amyloid beta peptide (Aβ) is recognised as a main feature of Alzheimer's disease (AD). Increasing evidence suggests that small soluble oligomers of Aβ are the toxic form of the peptide and may instigate AD. Different factors including some key residues within Aβ molecule, the cell membrane, prion protein and metals pl...
journal_title:Current medicinal chemistry
pub_type: 杂志文章,评审
doi:10.2174/0929867323666160229113911
更新日期:2016-01-01 00:00:00
abstract::RNA aptamers are non-coding small RNAs that bind to their cognate targets with high specificity and affinity. They are generally identified by iterative rounds of in vitro selection termed SELEX (Systemic Evolution of Ligands by Exponential Enrichment). Similar to antibodies, they can inhibit, modulate and disrupt the...
journal_title:Current medicinal chemistry
pub_type: 杂志文章,评审
doi:10.2174/0929867311320290011
更新日期:2013-01-01 00:00:00
abstract::The identification and characterisation of the isoenzyme cyclooxygenase 2 (COX-2) stimulated investigations to develop efficient non-steroidal anti-inflammatory drugs with reduced side effects compared to standard NSAIDs. This review will focus on the structural features needed to achieve COX-2 selectivity. Five struc...
journal_title:Current medicinal chemistry
pub_type: 杂志文章,评审
doi:10.2174/0929867003374237
更新日期:2000-11-01 00:00:00
abstract::The inhibition of protein degradation through the ubiquitin-proteasome pathway is a recently developed approach to cancer treatment which extends the range of cellular targets for chemotherapy. This therapeutic strategy is very interesting since the proteasomes carry out the regulated degradation of unnecessary or dam...
journal_title:Current medicinal chemistry
pub_type: 杂志文章,评审
doi:10.2174/092986708786848622
更新日期:2008-01-01 00:00:00
abstract::Fulvestrant is a novel endocrine therapy for breast cancer, with a unique structure and mode of action. It binds competitively to the oestrogen receptor (ER), with high affinity, and downregulates ER by functional blockade and increased turnover. Fulvestrant has reached the clinic via extensive pre-clinical and clinic...
journal_title:Current medicinal chemistry
pub_type: 杂志文章,评审
doi:10.2174/092986710790820633
更新日期:2010-01-01 00:00:00
abstract::Osteoporosis is a pathological loss of bone mass due to an imbalance in bone remodeling where osteoclast-mediated bone resorption exceeds osteoblast-mediated bone formation resulting in skeletal fragility and fractures. Anti-resorptive agents such as bisphosphonates and SERMs, and anabolic drugs that stimulate bone fo...
journal_title:Current medicinal chemistry
pub_type: 杂志文章
doi:10.2174/0929867327666200330142432
更新日期:2020-03-30 00:00:00
abstract:OBJECTIVES:Post-exercise cardiac troponin T (cTnT) release has been widely reported in adult athletes but limited data is available for adolescents. The aim of this study was to determine the incidence and magnitude of cTnT appearance in a large group of adolescent runners, and to determine any association between cTnT...
journal_title:Current medicinal chemistry
pub_type: 杂志文章
doi:10.2174/092986711796642625
更新日期:2011-01-01 00:00:00
abstract::The fibrinolytic system includes a broad spectrum of proteolytic enzymes with physiological and pathophysiological functions in several processes, such as haemostatic balance, tissue remodeling, tumor invasion, angiogenesis and reproduction. The main enzyme of the plasminogen activator system is plasmin, which is resp...
journal_title:Current medicinal chemistry
pub_type: 杂志文章,评审
doi:10.2174/092986708783955455
更新日期:2008-01-01 00:00:00
abstract::Functioning of G protein-coupled receptors (GPCRs) is tightly linked to the membrane environment, but a molecular level understanding of the modulation of GPCR by membrane lipids is not available. However, specific receptor-lipid interactions as well as unspecific effects mediated by the bulk properties of the membran...
journal_title:Current medicinal chemistry
pub_type: 杂志文章,评审
doi:
更新日期:2013-01-01 00:00:00
abstract::Recent advances in endoscopic techniques such as capsule endoscopy have revealed that aspirin and other nonsteroidal antiinflammatory drugs (NSAIDs) often cause mucosal lesions not only in the upper gastrointestinal tract, but also in the small intestine in humans. Gastric and duodenal lesions caused by NSAIDs can be ...
journal_title:Current medicinal chemistry
pub_type: 杂志文章,评审
doi:10.2174/092986712803413980
更新日期:2012-01-01 00:00:00
abstract::The development of bacterial resistance is a significant problem in the treatment of infection, and the importance of research directed toward the discovery of novel agents to treat infections cannot be underestimated. In the past, discovery programs have focused on modification of natural products or existing classes...
journal_title:Current medicinal chemistry
pub_type: 杂志文章,评审
doi:10.2174/0929867043364658
更新日期:2004-08-01 00:00:00
abstract::Antimicrobial resistance is an ever-increasing problem throughout the world and has already reached severe proportions. Two very common neglected tropical diseases are Chagas' disease and leishmaniasis. Chagas' disease is a severe health problem, mainly in Latin America, causing approximately 50000 deaths a year and m...
journal_title:Current medicinal chemistry
pub_type: 杂志文章
doi:10.2174/0929867325666171201101807
更新日期:2017-01-01 00:00:00
abstract::Poisoning of DNA topoisomerase I is the mechanism by which camptothecins interfere with tumor growth. Although the clinical use of camptothecins has had a significant impact on cancer therapy, de novo or acquired clinical resistance to these drugs is common. Clinical resistance to camptothecins is still a poorly under...
journal_title:Current medicinal chemistry
pub_type: 杂志文章,评审
doi:10.2174/0929867311320120006
更新日期:2013-01-01 00:00:00
abstract::A growing body of evidence has shown that oxidative stress may be involved in the development of vascular complications associated with diabetes. However, the molecular mechanism for increased reactive oxygen species (ROS) production in diabetes remains uncertain. Among various possible mechanisms, attention have incr...
journal_title:Current medicinal chemistry
pub_type: 杂志文章,评审
doi:10.2174/0929867033457133
更新日期:2003-09-01 00:00:00
abstract::Protein p53 is a key player in mitochondrial mediated apoptotic cell death and excess p53 activity has been implicated in many disease states such athrosclerosis, diabetes, osteoarthritis, Alzheimer's disease, Parkinson's disease, Huntington's disease, AIDS, P. falciparum and S. typhimurium infections. Thus, chemical ...
journal_title:Current medicinal chemistry
pub_type: 杂志文章,评审
doi:10.2174/092986709788681976
更新日期:2009-01-01 00:00:00
abstract::The vascular system distributes oxygen and nutrients to all tissues in the body. Additionally, the vascular system also functions in hosting and instructing tissue-specific stem and progenitor cells. Both cell- or blood-derived signals from the vascular system regulate stem cell properties in health and disease. Studi...
journal_title:Current medicinal chemistry
pub_type: 杂志文章,评审
doi:10.2174/0929867321666131227162215
更新日期:2014-01-01 00:00:00
abstract::Sarcomas are tumours of mesenchymal origin, which can arise in bone or soft tissues. They are rare but frequently quite aggressive and with a poor outcome. New approaches are needed to characterise these tumours and their resistance mechanisms to current therapies, responsible for tumour recurrence and treatment failu...
journal_title:Current medicinal chemistry
pub_type: 杂志文章,评审
doi:10.2174/0929867326666191212162102
更新日期:2020-01-01 00:00:00
abstract::Cellular signaling is regulated by several biochemical reactions, whose dynamics depends on changes in the fluxes of specific ligands through the containment barriers that are the biological membranes. The regulation of this complex dynamic equilibrium is mainly due to the activity of border proteins, that must be abl...
journal_title:Current medicinal chemistry
pub_type: 杂志文章,评审
doi:10.2174/092986710790980087
更新日期:2010-01-01 00:00:00