Abstract：
:The PI3K/Akt/mTOR pathway is the most frequently known activated aberrant pathway in human cancers. Pathologic activation can occur at multiple levels along the signaling pathway by a variety of mechanisms, including point mutations, amplifications, and inactivation of tumor suppressor genes. This pathway is also a known resistance pathway, as it can be activated by both receptor tyrosine kinases and other oncogenes. mTOR inhibitors were the first targeted molecules in this pathway, and have already been FDA-approved in multiple indications. Because of the broad potential applications of inhibiting this pathway upstream of mTOR, multiple compounds targeting PI3K are in development. In this review, we discuss the clinical development of these inhibitors, including dual PI3K/mTOR inhibitors, pan-PI3K inhibitors, and isoform-selective PI3K inhibitors. Common adverse events, including rash, nausea, vomiting, diarrhea, and hyperglycemia, have created a narrow therapeutic window for all classes of PI3K inhibitors. Furthermore, single agent clinical activity has also been limited, with the exception of isoform-selective inhibitors, particularly the PI3Kδ and PI3Kγ inhibitors in hematologic malignancies. The future role of inhibitors of the PI3K/Akt/mTOR pathway in the clinical practice of oncology likely depends on the development of patient selection strategies and the results of combination trials that are currently ongoing.
journal_name
Pharmacol Therjournal_title
Pharmacology & therapeuticsauthors
Bauer TM,Patel MR,Infante JRdoi
10.1016/j.pharmthera.2014.09.006subject
Has Abstractpub_date
2015-02-01 00:00:00pages
53-60eissn
0163-7258issn
1879-016Xpii
S0163-7258(14)00168-5journal_volume
146pub_type
杂志文章,评审abstract：:Hypoxia inducible factor (HIF) is an oxygen-sensitive transcription factor that enables aerobic organisms to adapt to hypoxia. This is achieved through the transcriptional activation of up to 200 genes, many of which are critical to cell survival. Under conditions of normoxia, the hydroxylation of HIF by prolyl hydrox...
journal_title：Pharmacology & therapeutics
pub_type： 杂志文章,评审
doi：10.1016/j.pharmthera.2012.07.005
更新日期：2012-10-01 00:00:00
abstract：:There are various receptor tyrosine kinase (TK)-targeted drugs that are currently used in the treatment of patients with non-small cell lung cancer (NSCLC). Among them, the epidermal growth factor receptor (EGFR) TK inhibitors (TKIs) are the most extensively studied. Receptor TKIs including EGFR TKIs have shown dramat...
journal_title：Pharmacology & therapeutics
pub_type： 杂志文章,评审
doi：10.1016/j.pharmthera.2016.03.002
更新日期：2016-05-01 00:00:00
abstract：:The demonstration that RNA can be cleaved by cis or trans ribozymes (catalytic RNAs, RNA enzymes) has potentially important therapeutic implications. Since their discovery in the 1980s, the biochemistry and conserved sequences of ribozymes have been well characterized. Ribozymes are effective modulators of gene expres...
journal_title：Pharmacology & therapeutics
pub_type： 杂志文章,评审
doi：10.1016/0163-7258(95)02008-x
更新日期：1995-01-01 00:00:00
abstract：:The understanding of renal fibrosis in chronic kidney disease (CKD) remains as a challenge. More than 10% of the population of developed countries suffer from CKD. Proliferation and activation of myofibroblasts and accumulation of extracellular matrix proteins are the main features of kidney fibrosis, a process in whi...
journal_title：Pharmacology & therapeutics
pub_type： 杂志文章,评审
doi：10.1016/j.pharmthera.2015.10.003
更新日期：2015-12-01 00:00:00
abstract：:High-mobility group box 1 (HMGB1) is one of the most abundant proteins in eukaryotes and the best characterized damage-associated molecular pattern (DAMP). The biological activities of HMGB1 depend on its subcellular location, context and post-translational modifications. Inside the nucleus, HMGB1 is engaged in many D...
journal_title：Pharmacology & therapeutics
pub_type： 杂志文章,评审
doi：10.1016/j.pharmthera.2018.12.005
更新日期：2019-04-01 00:00:00
abstract：:The selective 5-HT2C receptor agonist lorcaserin, in conjunction with lifestyle modification, was approved by the FDA in 2012 for weight management. It has been marketed in the US as Belviq® since 2013. This article provides a review of the preclinical and clinical pharmacology of lorcaserin, including its pharmacokin...
journal_title：Pharmacology & therapeutics
pub_type： 杂志文章,评审
doi：10.1016/j.pharmthera.2019.107417
更新日期：2020-01-01 00:00:00
abstract：:This review concerns the development of small molecule therapeutics for the inherited neurodegenerative disease Friedreich ataxia (FRDA). FRDA is caused by transcriptional repression of the nuclear FXN gene, encoding the essential mitochondrial protein frataxin and accompanying loss of frataxin protein. Frataxin insuf...
journal_title：Pharmacology & therapeutics
pub_type： 杂志文章,评审
doi：10.1016/j.pharmthera.2007.06.014
更新日期：2007-11-01 00:00:00
abstract：:Progranulin (PGRN) is abundantly expressed in epithelial cells, immune cells, neurons, and chondrocytes, and reportedly contributes to tumorigenesis. PGRN is a crucial mediator of wound healing and tissue repair. PGRN also functions as a neurotrophic factor and mutations in the PGRN gene resulting in partial loss of t...
journal_title：Pharmacology & therapeutics
pub_type： 杂志文章,评审
doi：10.1016/j.pharmthera.2011.10.003
更新日期：2012-01-01 00:00:00
abstract：:A number of neuronal functions, including synaptic plasticity, depend on proper regulation of synaptic proteins, many of which can be rapidly regulated by phosphorylation. Neuronal activity controls the function of these synaptic proteins by exquisitely regulating the balance of various protein kinase and protein phos...
journal_title：Pharmacology & therapeutics
pub_type： 杂志文章,评审
doi：10.1016/j.pharmthera.2006.06.003
更新日期：2006-12-01 00:00:00
abstract：:The coronavirus disease 2019 (COVID-19) pandemic is caused by a newly emerged coronavirus (CoV) called Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2). COVID-19 patients with cardiovascular disease (CVD) comorbidities have significantly increased morbidity and mortality. The use of angiotensin-converting ...
journal_title：Pharmacology & therapeutics
pub_type： 杂志文章,评审
doi：10.1016/j.pharmthera.2020.107628
更新日期：2020-11-01 00:00:00
abstract：:Atrial fibrillation (AF) is a growing clinical problem associated with increased morbidity and mortality. Development of safe and effective pharmacological treatments for AF is one of the greatest unmet medical needs facing our society. In spite of significant progress in non-pharmacological AF treatments (largely due...
journal_title：Pharmacology & therapeutics
pub_type： 杂志文章,评审
doi：10.1016/j.pharmthera.2011.08.002
更新日期：2011-12-01 00:00:00
abstract：:Heme, a complex of iron and protoporphyrin IX (PPIX), senses and utilizes oxygen in nearly all living cells. It is an essential component of various hemoproteins, including those involved in oxygen transport and storage (hemoglobin, myoglobin), electron transfer, drug and steroid metabolism (cytochromes), and signal t...
journal_title：Pharmacology & therapeutics
pub_type： 杂志文章,评审
doi：10.1016/j.pharmthera.2007.02.001
更新日期：2007-06-01 00:00:00
abstract：:There is clear evidence that CB(2), historically referred to as the peripheral cannabinoid receptor, mediates many of the immune modulatory effects of cannabinoids. However, cannabinoid receptors cannot be classified simply as central or peripheral since CB(2) has been shown to play a role in the central nervous syste...
journal_title：Pharmacology & therapeutics
pub_type： 杂志文章,评审
doi：10.1016/j.pharmthera.2012.12.004
更新日期：2013-03-01 00:00:00
abstract：:Preliminary investigations of the physical properties of oligonucleotide analogs that contain alternating methylphosphonate/phosphodiester linkages are described. An alternating oligo-2'-O-methylribonucleoside methylphosphonate, oligomer 1676, whose sequence is complementary to the upper hairpin region of human immuno...
journal_title：Pharmacology & therapeutics
pub_type： 杂志文章,评审
doi：10.1016/s0163-7258(99)00054-6
更新日期：2000-03-01 00:00:00
abstract：:Integrins are heterodimeric cell surface receptors, which principally mediate the interaction between cells and their extracellular microenvironments. Because of their pivotal roles in cancer proliferation, survival, invasion and metastasis, integrins have been recognized as promising targets for cancer treatment. As ...
journal_title：Pharmacology & therapeutics
pub_type： 杂志文章,评审
doi：10.1016/j.pharmthera.2013.05.007
更新日期：2013-10-01 00:00:00
abstract：:Statins are effective drugs to reduce cardiovascular events secondary to dyslipidemia; however, they cause frequent undesirable side effects. The incidence of statin-induced myotoxicity (SIM) is presented by 7 to 29% of patients, depending upon the report. SIM may develop in presence of abnormally high concentrations ...
journal_title：Pharmacology & therapeutics
pub_type： 杂志文章,评审
doi：10.1016/j.pharmthera.2017.02.029
更新日期：2017-07-01 00:00:00
abstract：:Three separate experimental approaches, using site-selective cAMP analogs, antisense strategy and retroviral vector-mediated gene transfer, have provided evidence that two isoforms, the RI- and RII-regulatory subunits of cAMP-dependent protein kinase, have opposite roles in cell growth and differentiation; RI being gr...
journal_title：Pharmacology & therapeutics
pub_type： 杂志文章,评审
doi：10.1016/0163-7258(93)90010-b
更新日期：1993-11-01 00:00:00
abstract：:For many years, warfarin was the only effective oral anticoagulant to prevent and treat thromboembolism. Nevertheless, its clinical use is limited by a narrow therapeutic window, extensive drug interactions, need of strict dietary control and frequent monitoring. The pharmacological response is also unpredictable and ...
journal_title：Pharmacology & therapeutics
pub_type： 杂志文章,评审
doi：10.1016/j.pharmthera.2010.09.005
更新日期：2011-02-01 00:00:00
abstract：:Neuropeptides are the largest class of intercellular signaling molecules, contributing to a wide variety of physiological processes. Neuropeptide receptors are therapeutic targets for a broad range of drugs, including medications to treat pain, addiction, sleep disorders, and nausea. In addition to >100 peptides with ...
journal_title：Pharmacology & therapeutics
pub_type： 杂志文章,评审
doi：10.1016/j.pharmthera.2017.11.006
更新日期：2018-05-01 00:00:00
abstract：:Cardiac fibrosis is a pathogenic factor of many cardiovascular diseases (CVD), which seriously affects people's life, and health and causes huge economic losses. Increasing evidence has shown that peroxisome proliferator-activated receptors (PPARs) can regulate the progression of cardiac fibrosis. For the first time, ...
journal_title：Pharmacology & therapeutics
pub_type： 杂志文章,评审
doi：10.1016/j.pharmthera.2020.107702
更新日期：2020-10-04 00:00:00
abstract：:Primaquine is the only antimalarial drug available to clinicians for the treatment of relapsing forms of malaria. Primaquine development and usage dates back to the 1940s and has been administered to millions of individuals to treat and eliminate malaria infections. Primaquine therapy is not without disadvantages, how...
journal_title：Pharmacology & therapeutics
pub_type： 杂志文章,评审
doi：10.1016/j.pharmthera.2016.03.011
更新日期：2016-05-01 00:00:00
abstract：:Sphingolipid metabolites, such as ceramide, sphingosine and sphingosine-1-phosphate (S1P), play many important roles in cellular activities. Ceramide and sphingosine inhibit cell proliferation and induce cell apoptosis while S1P has the opposite effect. Maintaining a metabolic balance of sphingolipids is essential for...
journal_title：Pharmacology & therapeutics
pub_type： 杂志文章,评审
doi：10.1016/j.pharmthera.2018.10.011
更新日期：2019-03-01 00:00:00
abstract：:Synaptic inhibition plays a key role in regulating neuronal excitability and information processing in the brain. The strength of synaptic inhibition is therefore an important determinant of both cellular and network activity levels in the central nervous system (CNS). gamma-aminobutyric acid type A (GABA(A)) receptor...
journal_title：Pharmacology & therapeutics
pub_type： 杂志文章
doi：10.1016/j.pharmthera.2009.03.012
更新日期：2009-07-01 00:00:00
abstract：:Mesenchymal stem cells (MSCs) are multipotent tissue stem cells that differentiate into a number of mesodermal tissue types, including osteoblasts, adipocytes, chondrocytes and myofibroblasts. MSCs were originally identified in the bone marrow (BM) of humans and other mammals, but recent studies have shown that they a...
journal_title：Pharmacology & therapeutics
pub_type： 杂志文章,评审
doi：10.1016/j.pharmthera.2019.04.005
更新日期：2019-08-01 00:00:00
abstract：:Protein kinases recognize and bind to specific amino acid sequences on their protein substrates. These sequences can be readily identified using combinatorial peptide libraries. Unfortunately, conventional peptide libraries are not designed to identify subtle structural factors that can dramatically enhance enzyme aff...
journal_title：Pharmacology & therapeutics
pub_type： 杂志文章,评审
doi：10.1016/s0163-7258(02)00187-0
更新日期：2002-02-01 00:00:00
abstract：:Experimental and clinical studies suggest that the central and peripheral benzodiazepine (BDZ) receptors together with their ligands form the molecular basis of a novel regulatory network that contributes to the effects of anxiety on immune status. The peripheral-type receptors located on phagocytes and glial cells ap...
journal_title：Pharmacology & therapeutics
pub_type： 杂志文章,评审
doi：10.1016/s0163-7258(97)00055-7
更新日期：1997-09-01 00:00:00
abstract：:Unwanted cells are removed by physiological cell death processes that are highly conserved throughout the animal kingdom. Physiological cell death plays an important role in development, tissue homeostasis and defence against viral infection and mutation. This review describes the molecular components that implement t...
journal_title：Pharmacology & therapeutics
pub_type： 杂志文章,评审
doi：10.1016/s0163-7258(96)00098-8
更新日期：1996-01-01 00:00:00
abstract：:Despite difficulties in the interpretation of available data, certain general observations can be made on the epidemiology of poisioning. Childhood poisoning is usually accidental and tends to be associated with a low morbidity and mortality. In Western Europe and North America, it is most often due to household produ...
journal_title：Pharmacology & therapeutics
pub_type： 杂志文章,评审
doi：10.1016/0163-7258(93)90069-p
更新日期：1993-09-01 00:00:00
abstract：:Proarrhythmic susceptibility to drug-induced Torsades de Pointes is restricted to individuals with a predisposed phenotype characterized by a reduced repolarization reserve. Additional factors are often involved in a further impairment of repolarization, possibly culminating with dangerous ventricular polymorphic tach...
journal_title：Pharmacology & therapeutics
pub_type： 杂志文章,评审
doi：10.1016/j.pharmthera.2008.03.006
更新日期：2008-08-01 00:00:00
abstract：:Although the existence of halogenated lipids in lower organisms has been known for many years, it is only since the 1990s that interest in their occurrence in mammalian systems has developed. Chlorinated (and other halogenated) lipids can arise from oxidation by hypohalous acids, such as HOCl, which are products of th...
journal_title：Pharmacology & therapeutics
pub_type： 杂志文章,评审
doi：10.1016/j.pharmthera.2007.06.002
更新日期：2007-09-01 00:00:00
