Therapeutic Potential of Phosphoinositide 3-Kinase Inhibitors

Ward, Stephen G.; Sotsios, Yannis; Dowden, James; Bruce, Ian; Finan, Peter M.

doi:10.1016/s1074-5521(03)00048-6

Cited by 123 publications

(80 citation statements)

References 52 publications

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“…PIK3CA mutation may define a subset of esophageal tumors that respond differently to current treatment approaches or identify tumors that could be candidates for alternative therapies that specifically target the PI3K pathway. [12][13][14] In summary, this is the first investigation of PIK3CA and PIK3CB mutations in esophageal cancer. Our data extends previous studies suggesting that the acquisition of PIK3CA mutations may be an important molecular event in the etiology of a wide range of tumor types and highlighting the potential broad applicability that PI3K pathway inhibitors may have in the treatment of human cancers.…”

Section: Pi3k Mutations In Esophageal Cancersmentioning

confidence: 84%

“…[12][13][14] In addition, there is increasing evidence that PI3K inhibitors can enhance the efficacy of conventional chemotherapeutic agents in both in vitro and in vivo models. 13,14 Since tumors harbouring mutations in PI3K are likely to be more susceptible to the therapeutic actions of agents that target the PI3K pathway, it is possible that the presence of PI3K mutations may be a useful diagnostic/prognostic indicator to aid in the selection of appropriate treatment protocols for individual patients. It is thus important to establish the frequency of PI3K mutations in a wider range of human tumors.…”

mentioning

confidence: 99%

“…[6][7][8][9][10][11] Therapeutic strategies that target PI3K or its downstream targets such as Akt and mTOR are beginning to show considerable promise as potential new anticancer treatments. [12][13][14] In addition, there is increasing evidence that PI3K inhibitors can enhance the efficacy of conventional chemotherapeutic agents in both in vitro and in vivo models. 13,14 Since tumors harbouring mutations in PI3K are likely to be more susceptible to the therapeutic actions of agents that target the PI3K pathway, it is possible that the presence of PI3K mutations may be a useful diagnostic/prognostic indicator to aid in the selection of appropriate treatment protocols for individual patients.…”

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confidence: 99%

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Mutation analysis of PIK3CA and PIK3CB in esophageal cancer and Barrett's esophagus

Phillips

Russell

Ciavarella

et al. 2006

Intl Journal of Cancer

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Mutation of PIK3CA, the gene coding for the p110a catalytic subunit of phosphoinositide 3-kinase (PI3K), has been reported in a limited range of human tumors. We now report that PIK3CA is also mutated in esophageal tumors. Single-strand conformational polymorphism (SSCP) and denaturing high-performance liquid chromatography (DHPLC) were used to screen all 20 exons of PIK3CA in 101 samples from 95 individuals with esophageal cancer and/or Barrett's esophagus. Somatic mutation of PIK3CA was detected in 4 of 35 (11.8%) of esophageal squamous cell carcinomas (SCC) and 3 of 50 (6%) adenocarcinomas. No mutations were detected in any of 17 samples of Barrett's esophagus. For PIK3CB, we screened exons 11 and 22, which code for the regions corresponding to the exon 9 and 20 mutational ÔhotspotsÕ of PIK3CA. No somatic changes were detected in PIK3CB This study extends previous observations in other tumor types by demonstrating the presence of somatic PIK3CA mutations in both SCC and adenocarcinoma of the esophagus, thus implicating the PI3K pathway in the initiation and/or progression of esophageal cancers. ' 2005 Wiley-Liss, Inc.Key words: phosphatidylinositide 3 0 -kinase; mutation; oncogene; esophageal cancer; Barrett's esophagus Phosphatidylinositide 3-kinases (PI3K) are a ubiquitous family of lipid kinases that catalyse the phosphorylation of phosphatidylinositol (PI), PI(4)P and PI(4,5)P 2 forming PI(3)P, PI(3,4)P 2 and PI(3,4,5)P 3 , respectively. 1 These lipid products are then able to activate a variety of downstream targets that regulate a wide range of important cellular processes, including cell proliferation, migration and survival, oncogenic transformation and intracellular trafficking of proteins. Of the PI3Ks, the most extensively studied are the class 1A sub-group, which exist as heterodimers consisting of a unique catalytic subunit (p110a, b, and d) along with one of a number of shared regulatory subunits (p85a, p85b and p55g). 1,2 Numerous genetic and functional studies have clearly established a fundamental role for the PI3K pathway in the development of neoplasia. Amplification of the PIK3CA gene (which codes for the p110a catalytic subunit of PI3K) has been reported in a number of different tumor types. 3,4 We have previously reported activating somatic mutations in the p85a regulatory subunit of PI3K (PIK3R1) in primary ovarian and colon tumors, 5 while more recently we, and others, have demonstrated a high frequency of somatic mutations in PIK3CA in a limited selection of tumor types. [6][7][8][9][10][11] Therapeutic strategies that target PI3K or its downstream targets such as Akt and mTOR are beginning to show considerable promise as potential new anticancer treatments. [12][13][14] In addition, there is increasing evidence that PI3K inhibitors can enhance the efficacy of conventional chemotherapeutic agents in both in vitro and in vivo models. 13,14 Since tumors harbouring mutations in PI3K are likely to be more susceptible to the therapeutic actions of agents that target the PI3K pathway, it i...

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Section: Pi3k Mutations In Esophageal Cancersmentioning

confidence: 84%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Mutation analysis of PIK3CA and PIK3CB in esophageal cancer and Barrett's esophagus

Phillips

Russell

Ciavarella

et al. 2006

Intl Journal of Cancer

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“…PI3K3CA mutations have been found in colorectal, glioblastoma, gastric, and breast cancers (Bachman et al 2004;Samuels et al 2004). Together with previous evidence for amplification of PIK3CA (Shayesteh et al 1999) and a wealth of other data, these mutation studies add support for the development of PI3K inhibitors for cancer treatment (Stein and Waterfield 2000;Vivanco and Sawyers 2002;Ward et al 2003;Drees et al 2004;Workman 2004a). This is addressed in a later section.…”

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confidence: 85%

Drugging the Cancer Kinome: Progress and Challenges in Developing Personalized Molecular Cancer Therapeutics

Workman¹

2005

Cold Spring Harbor Symposia on Quantitative Biology

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A major goal of cancer research is to translate our understanding of the causation of malignancy at the level of the genome and biochemical pathways into the development of drugs with improved activity and cancer selectivity. This paper provides a personal perspective of the current status of efforts to achieve this goal, with a particular focus on drugging the cancer kinome. Remarkable progress has been made in this area, but many challenges remain. The value of cancer kinome sequencing is emphasized. Three projects in which the author's laboratory is involved are reviewed in detail. These involve the discovery and development of inhibitors of cyclin-dependent kinases, phosphoinositide 3-kinases, and the Hsp90 molecular chaperone.ples from our own recent experience in developing smallmolecule inhibitors against three molecular targets, namely cyclin-dependent kinases (CDKs), phosphoinositide 3-kinase (PI3Ks), and the Hsp90 molecular chaperone. The reader is also referred to previous personal views from this author in published interviews (Workman 2001(Workman , 2003c. CANCER KINOME TARGETSOncogenic kinases clearly punch above their weight in the league tables of cancer genes. Of the 291 cancer-causing genes identified in a recent census, 27 (6%) encode protein kinase domains, much higher than the 6 (2%) that would be predicted on the basis of random selection (Futreal et al. 2004). The druggability of kinases as a target class is confirmed by the examples listed in the previous section of this paper. As mentioned, both antibodybased and small-molecule approaches to drugging the cancer kinome have been successful. Kinases now represent the most frequently targeted gene classes in cancer and are second only to G-protein-coupled receptors when ranked across all therapeutic areas (Cohen 2002;Hopkins and Groom 2002).This has stimulated interest to search for new drug targets among the 518 putative kinases in the human genome (Cohen 2002;Manning et al. 2002). The earliest kinase targets represented the results of decades of painstaking biological research. On the basis of a large body of work, we now know that kinases can be activated in cancer by mutation, translocation, amplification, overexpression, and posttranslational modification. The discovery of kinase targets has recently benefited from the availability of the complete human genome sequence (International Human Genome Sequencing Consortium 2004) and the application of gene expression profiling by microarray, together with high-throughput mutation detection and high-throughput sequencing approaches (Weir et al. 2004;.In the first breakthrough made by high-throughput cancer genome sequencing, activating mutations in B-RAF were identified, particularly in melanoma but also in papillary thyroid, serous ovarian, and other cancers (Davies et al. 2002;Garnett and Marais 2004). This discovery immediately stimulated the evaluation in malignant melanoma of sorafenib (formerly known as BAY 43-9006; see Fig. 2), a multi-targeted kinase inhibitor that blocks B-RAF and ...

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“…虽然其活性比渥曼青霉素 [2] (Wortmannin, . 鉴于其广泛的生理活性, 使得它成为治疗炎症、免疫紊乱、癌症以及心血管疾病的药物潜在的替代物 [3] . 由于 Liphagal 具有一个新奇的 [6-7- [7] .…”

Section: 引言unclassified

Studies on the Total Synthesis of 8-epi-Liphagal

彭金宝¹,

后小军²,

张书宇³

et al. 2012

Acta Chim. Sinica

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The tetracyclic meroterpenoid natural product (＋)-liphagal is one of a number of natural inhibitors of phosphatidylinositol 3-kinase (PI3K), which plays a central role in regulation of cell proliferation, cell survival, adhesion, membrane trafficking, glucose transport and neurite growth. Liphagal also shows inhibitory activity against PI3Kα with an IC 50 of 100 nmol•L -1 making it as an agent for the treatment of inflammatory and autoimmune disorders as well as cancer and cardiovascular diseases. From a structural point of view, liphagal has an unprecedented [6-7-5-6] tetracyclic skeleton, and has attracted significant attention from the synthetic chemists. Starting from cheap and commercially available 2,4,5-trimethoxylbenzaldehyde and α-ionone, an advanced intermediate 10 for the synthesis of 8-epi-liphagal was achieved in the longest linear 7 steps and 8.72% yield. The key reactions include: Wittig reaction, Cu-catalyzed cyclization, chemoselective hydrogenation and Friedel-Crafts reaction.

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Therapeutic Potential of Phosphoinositide 3-Kinase Inhibitors

Cited by 123 publications

References 52 publications

Mutation analysis of PIK3CA and PIK3CB in esophageal cancer and Barrett's esophagus

Mutation analysis of PIK3CA and PIK3CB in esophageal cancer and Barrett's esophagus

Drugging the Cancer Kinome: Progress and Challenges in Developing Personalized Molecular Cancer Therapeutics

Studies on the Total Synthesis of 8-epi-Liphagal

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