PI3K inhibitors: review and new strategies

Zhang, Mingzhen; Jang, Hyunbum; Nussinov, Ruth

doi:10.1039/d0sc01676d

Cited by 127 publications

(109 citation statements)

References 126 publications

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“…To investigate the PI3K/AKT pathway, cells prepared as above were pre-treated for 1 h with LY294002 (5 µM). This inhibitor was chosen as it inhibits all class I PI3Ks, which are the most relevant for cell physiology [ 50 ]. Mycoplasma testing was routinely done with the N-GARDE Mycoplasma PCR Reagent set (Euro Clone, cat.…”

Section: Methodsmentioning

confidence: 99%

The PI3K/AKT Pathway Is Activated by HGF in NT2D1 Non-Seminoma Cells and Has a Role in the Modulation of Their Malignant Behavior

Gesualdi

Leonetti

Cucina

et al. 2020

IJMS

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Overactivation of the c-MET/HGF system is a feature of many cancers. We previously reported that type II testicular germ cell tumor (TGCT) cells express the c-MET receptor, forming non-seminomatous lesions that are more positive compared with seminomatous ones. Notably, we also demonstrated that NT2D1 non-seminomatous cells (derived from an embryonal carcinoma lesion) increase their proliferation, migration, and invasion in response to HGF. Herein, we report that HGF immunoreactivity is more evident in the microenvironment of embryonal carcinoma biopsies with respect to seminomatous ones, indicating a tumor-dependent modulation of the testicular niche. PI3K/AKT is one of the signaling pathways triggered by HGF through the c-MET activation cascade. Herein, we demonstrated that phospho-AKT increases in NT2D1 cells after HGF stimulation. Moreover, we found that this pathway is involved in HGF-dependent NT2D1 cell proliferation, migration, and invasion, since the co-administration of the PI3K inhibitor LY294002 together with HGF abrogates these responses. Notably, the inhibition of endogenous PI3K affects collective cell migration but does not influence proliferation or chemotactic activity. Surprisingly, LY294002 administered without the co-administration of HGF increases cell invasion at levels comparable to the HGF-administered samples. This paradoxical result highlights the role of the testicular microenvironment in the modulation of cellular responses and stimulates the study of the testicular secretome in cancer lesions.

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Section: Methodsmentioning

confidence: 99%

The PI3K/AKT Pathway Is Activated by HGF in NT2D1 Non-Seminoma Cells and Has a Role in the Modulation of Their Malignant Behavior

Gesualdi

Leonetti

Cucina

et al. 2020

IJMS

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“…The safety profile of inhibitors is acceptable [77]. Single-agent PI3K inhibitor does not present a potent effect like EGFR-TKI and works on the selected tumor [77][78][79][80]. FDA only approves alpelisib for breast cancer in PI3K mutated breast cancer and paxalisib for DIPG.…”

Section: Pi3k Inhibitors Are Promising But Still Have a Long Way To Gomentioning

confidence: 99%

“…Scholars note that PIK3CA mutations often coexist with KRAS and BRAF mutations [94]. A parallel oncogenic pathway activation abrogates the effects of PI3K/Akt/mTOR inhibitors [77,79]. Vemurafenib and dabrafenib are two successful drugs targeting BRAF; however, they present a very modest effect and only last 6 months PFS [95][96][97][98].…”

Section: Synthetic Lethal With Pi3k Inhibitors May Be Highlighted Formentioning

confidence: 99%

Therapeutic strategies of different HPV status in Head and Neck Squamous Cell Carcinoma

Sun¹,

Wang²,

Qiu³

et al. 2021

Int. J. Biol. Sci.

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Head and neck squamous cell carcinoma (HNSCC) is the 9 th most common malignant tumor in the world. Based on the etiology, HNSCC has two main subtypes: human papillomavirus (HPV)-related and HPV-unrelated. HPV-positive HNSCC is more sensitive to treatment with favorable survival. Due to the different biological behaviors, individual therapy is necessary and urgently required to deduce the therapeutic intensity of HPV-positive disease and look for a more effective and toxicity-acceptable regimen for HPV-negative disease. EGFR amplification and PI3K/AKT/mTOR pathway aberrant activation are quite common in HPV-positive HNSCC. Besides, HPV infection alters immune cell infiltrating in HNSCC and encompasses a diverse and heterogeneous landscape with more immune infiltration. On the other hand, the chance of HPV-negative cancers harboring mutation on the P53 gene is significantly higher than that of HPV-positive disease. This review focuses on the updated preclinical and clinical data of HPV-positive and HPV-negative HNSCC and discusses the therapeutic strategies of different HPV status in HNSCC.

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“…The selection of PI3Kδ can be related with the expression pattern of this isoform, which is restricted to immune system. The PI3Kα is widely expressed in the body and also is related with the insulin signaling pathway and is related with the hyperglycemia [29,30,32] . They observed that the carbonyl and fluoro group in the quinazolinone extended into the solvent exposed region and enabled the introduction of the HDAC pharmacophore (linker and zinc binding group) [119] (Figure 11).…”

Section: Exploring Selectivity In Multitarget Hdac and Pi3k Inhibitorsmentioning

confidence: 99%

“…PI3Ks are a family of lipid kinases that integrate signals that regulate multiple signaling pathways in several cellular processes, such as cell proliferation, growth, survival, motility and metabolism [28–32] . Changes that cause PI3K overactivation are frequently found in many types of cancer, which makes this class of enzymes an interesting target for the development of new inhibitors as a promising anticancer therapy [33–36] .…”

Section: Introductionmentioning

confidence: 99%

Multitarget Inhibition of Histone Deacetylase (HDAC) and Phosphatidylinositol‐3‐kinase (PI3K): Current and Future Prospects

2020

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The discovery of histone deacetylase (HDAC) inhibitors is a hot topic in the medicinal chemistry community regarding cancer research. This is related primarily to two factors: success in the clinic, e. g., the four FDA‐approved HDAC inhibitors, and strong versatility to combine their pharmacophoric features to design new hybrid compounds with multitarget profiles. Thus, the selection of adequate pharmacophores to combine, i. e., combining targets that can result in a synergistic effect, is desirable, as it increases the probability of discovering a new useful therapeutic strategy. In this work, we highlight the design of multitarget HDAC/PI3K inhibitors. Although this approach is still in its early stages, many significant works have described the design and pharmacological evaluation of this new promising class of multitarget inhibitors, where compound CUDC‐907, which is already in clinical trials, stands out. Therefore, the question emerges of whether there still space for the design and evaluation of new multitarget HDAC/PI3K inhibitors. When considering the selectivity profile of the described multitarget compounds, the answer appears to be in the affirmative, especially since the first examples of compounds with a certain selectivity profile only recently appeared in 2020.

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PI3K inhibitors: review and new strategies

Abstract: The search is on for effective specific inhibitors for PI3Kα mutants.

Cited by 127 publications

References 126 publications

The PI3K/AKT Pathway Is Activated by HGF in NT2D1 Non-Seminoma Cells and Has a Role in the Modulation of Their Malignant Behavior

The PI3K/AKT Pathway Is Activated by HGF in NT2D1 Non-Seminoma Cells and Has a Role in the Modulation of Their Malignant Behavior

Therapeutic strategies of different HPV status in Head and Neck Squamous Cell Carcinoma

Multitarget Inhibition of Histone Deacetylase (HDAC) and Phosphatidylinositol‐3‐kinase (PI3K): Current and Future Prospects

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