Class I phosphatidylinositol 3-kinase inhibitors for cancer therapy

Wenyuan, Zhao; Qiu, Yuling; Kong, Dexin

doi:10.1016/j.apsb.2016.07.006

Cited by 128 publications

(93 citation statements)

References 101 publications

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“…The PI3K/AKT/mTOR pathway is frequently activated in cSCC, compared to actinic keratosis or normal skin (47). Class I PI3Ks phosphorylate phosphatidylinositol 4,5-bisphosphate (PIP2) at the 3-OH of the inositol ring to generate phosphatidylinositol 3,4,5-trisphosphate (PIP3), which in turn activates AKT and the downstream mTOR complex to play key roles in carcinogenesis (48). Activation of AKT will generate downstream effects, including the promotion of cell proliferation, migration and invasion, increasing cellular glycolytic flux and inhibiting cellular apoptosis (49).…”

Section: Discussionmentioning

confidence: 99%

“…6). As a result, inhibitors of PI3K/AKT/mTOR have been explored, among which a selective p110 inhibitor, idelalisib, in PIK3CA mutation-positive cancer has been approved for the treatment of chronic lymphocytic leukemia (CLL) and follicular B-cell lymphoma of non-Hodgkin's lymphoma (48). However, no clinical studies have reported the role of PI3K/AKT pathway-targeting drugs in cSCC to date.…”

Section: Discussionmentioning

confidence: 99%

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Text mining‑based drug discovery in cutaneous squamous cell carcinoma

2018

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Cutaneous squamous cell carcinoma (cSCC) is one of the most common skin cancers. However, the efficacy and utility of the available drug therapies are limited. The objective of the present study was to determine the genes and molecular pathways associated with cSCC by using computational tools and publicly available data, and to explore drugs targeting the relevant molecular pathways for cSCC treatment. In this study, we used text mining and GeneCodis to mine genes which were highly related to cSCC. Protein-protein interaction (PPI) analysis was performed by using STRING and Cytoscape. By using the data analytical tool cBioPortal, we analyzed the characteristics of candidate genes for the purpose of drug selection. Based on the drug-gene interaction analysis of the final genes, candidate drugs were then derived. Our analysis identified 121 genes related to cSCC from the text mining searches. Gene enrichment analysis yielded 11 genes representing 10 pathways, targetable by a total of 55 drugs as possible drug treatments for cSCC. The final list included 25 chemotherapy agents, 21 tyrosine kinase inhibitors (TKIs), 7 PI3K/AKT/mTOR inhibitors, 2 MAPK inhibitors, 2 cyclin-dependent kinase (CDK) inhibitors, 1 histone deacetylase (HDAC) inhibitor, 3 nonsteroidal anti-inflammatory drugs (NSAIDs) and 3 other drugs, which directly affect the most enriched pathways. In conclusions, drug discovery using in silico text mining and pathway analysis tools may be a method of exploring candidate drugs which target the genes/pathways relevant to cSCC, to identify potential treatments.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Text mining‑based drug discovery in cutaneous squamous cell carcinoma

2018

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“…The inhibition of this enzyme showed potent anticancer activity, but until now all the reported PI 3 K inhibitors such as GDC‐0941 or pictilisib ( 57 ) showed elevated resistance rates render its use as single agent is not suitable for combating cancer. As a result, it is used in combination with other pathways inhibitors to target multiple pathways . On the other hand, it was found that the combination index between pictilisib ( 57 ) and the HDAC inhibitor SAHA is less than one proving their synergism .…”

Section: Design Of Dual Pi3k/hdac Inhibitorsmentioning

confidence: 99%

“…As a result, it is used in combination with other pathways inhibitors to target multiple pathways. 65 On the other hand, it was found that the combination index between pictilisib (57) and the HDAC inhibitor SAHA is less than one proving their synergism. 66 As a result, Qian et al 66 developed the first chimeric HDAC /PI 3 K inhibitor hybrid 58 or called CUDC-907 ( Figure 17).…”

Section: Design Of Dual C-met/hdac Inhibitorsmentioning

confidence: 99%

Chimeric HDAC inhibitors: Comprehensive review on the HDAC‐based strategies developed to combat cancer

Hesham

Lasheen

Abouzid

2018

Medicinal Research Reviews

120

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Recently, molecular hybridization paradigm became an interesting and smart way to defeat the multifaceted cancer disease by a single molecular entity that acts via several mechanisms just like a magic bullet. Also, HDAC is an important epigenetic target in drug discovery, and the HDAC inhibitors showed successful pattern as cytotoxic agents. Because of their flexible structure activity relationship, it was easy to link them to other anticancer scaffolds. So, many dual action HDAC inhibitors have been developed and most of these hybrids have higher potency than the constituting parents in fighting of the cancer cells. This review describes potential applications of chimeric HDAC inhibitors, which simultaneously modulate not only HDAC but also multiple targets, in treatment of relapsing and drug-resistant cancers. We have nearly collected most of the reported dual action HDAC inhibitors yet to provide a comprehensive guide for the drug discovery process for developing more efficient anticancer agents.

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“…While PI3Kd and PI3Kg are well known to be involved in the immune system and inflammation (15,16), PI3Kd-specific inhibitors have demonstrated antitumor effects. In particular, idelalisib (CAL101) has become the first approved PI3K inhibitor for treatment of patients with relapsed chronic lymphocytic leukemia (17). We previously reported that the pan-PI3K inhibitor ZSTK474 exhibited antimetastatic effects via blocking migration and suppressing matrix metalloproteinase secretion of prostate cancer PC3 cells (18).…”

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confidence: 99%

Phosphatidylinositol 3‐kinase β and β isoforms play key roles in metastasis of prostate cancer DU145 cells

et al. 2018

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Metastasis is the main cause of the lethality of prostate cancer. Class I phosphatidylinositol 3‐kinases (PI3Ks), which contain 4 isoforms, α, β, δ, and γ, are known to play important roles in cell growth, migration, invasion, and so on. However, the respective role of each PI3K isoform in cancer cell migration and invasion remains unknown. In a study that aimed to elucidate the respective role of the 4 PI3K isoforms, we investigated the change in migratory and invasive ability of DU145 cells after treatment with each PI3K isoform‐specific inhibitor. Both migration and invasion of DU145 cells were potently blocked by each of the PI3Kβ inhibitors (GSK2636771 and TGX221) and PI3Kδ inhibitors (CAL101 and IC87114) while not obviously affected by PI3Kα inhibitor BYL719 or PI3Kγ inhibitor AS252424. Furthermore, knocking down PI3Kβ or PI3Kδ isoform led to a significant decrease in migration of DU145. The results suggest that PI3Kβ and PI3Kδ play key roles in prostate cancer cell migration, while PI3Kα and PI3Kγ might be redundant. Oral administration of GSK2636771 (100 mg/kg) and CAL101 (30 mg/kg) inhibited tumor growth in bone, an experimental model by intratibia injection of DU145 cells, with improved bone structure and bone mineral density analyzed by micro‐computed tomography. Tissue staining indicated reduction of metastatic DU145 cells and osteoclasts in the bones of GSK2636771‐ and CAL101‐treated mice compared to the untreated group. In summary, our results indicated the distinct roles of 4 PI3K isoforms in the migration of prostate cancer DU145 cells, and they demonstrated the in vitro and in vivo antimetastatic effect of PI3K‐isoform specific inhibitors, most of which are in clinical trials.—Zhang, Z., Liu, J., Wang, Y., Tan, X., Zhao, W., Xing, X., Qiu, Y., Wang, R., Jin, M., Fan, G., Zhang, P., Zhong, Y., Kong, D. Phosphatidylinositol 3‐kinase β and δ isoforms play key roles in metastasis of prostate cancer DU145 cells. FASEB J. 32, 5967–5975 (2018). http://www.fasebj.org

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Class I phosphatidylinositol 3-kinase inhibitors for cancer therapy

Cited by 128 publications

References 101 publications

Text mining‑based drug discovery in cutaneous squamous cell carcinoma

Text mining‑based drug discovery in cutaneous squamous cell carcinoma

Chimeric HDAC inhibitors: Comprehensive review on the HDAC‐based strategies developed to combat cancer

Phosphatidylinositol 3‐kinase β and β isoforms play key roles in metastasis of prostate cancer DU145 cells

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