Design, synthesis and biological evaluation of novel 4-aminoquinazolines as dual target inhibitors of EGFR-PI3Kα

Ding, Huaiwei; Deng, Chenglong; Li, Dandan; Liu, Dandan; Chai, Shao-Meng; Wang, Wei; Zhang, Yan; Chen, Kai; Li, Xin; Wang, Jian; Song, Shao‐Jiang; Song, Haiyan

doi:10.1016/j.ejmech.2018.01.081

Cited by 18 publications

(10 citation statements)

References 20 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…According to molecular docking studies, both CFM4.16 and CFM4.17 have been shown to bind with EGFR's ATP binding site [6]. This is consistent with the work of other investigators who have demonstrated that compounds with the ability to target numerous components in the EGFR signaling cascade are more inhibited than those with only one target [23].…”

Section: Introductionsupporting

confidence: 86%

Combined Transcriptomic and Proteomic Profiling to Unravel Osimertinib, CARP-1 Functional Mimetic (CFM 4.17) Formulation and Telmisartan Combo Treatment in NSCLC Tumor Xenografts

et al. 2022

View full text Add to dashboard Cite

The epidermal growth factor receptor (EGFR) is highly expressed in many non-small cell lung cancers (NSCLC), necessitating the use of EGFR-tyrosine kinase inhibitors (TKIs) as first-line treatments. Osimertinib (OSM), a third-generation TKI, is routinely used in clinics, but T790M mutations in exon 20 of the EGFR receptor lead to resistance against OSM, necessitating the development of more effective therapeutics. Telmisartan (TLM), OSM, and cell cycle and apoptosis regulatory protein 1 (CARP-1) functional mimetic treatments (CFM4.17) were evaluated in this study against experimental H1975 tumor xenografts to ascertain their anti-cancer effects. Briefly, tumor growth was studied in H1975 xenografts in athymic nude mice, gene and protein expressions were analyzed using next-generation RNA sequencing, proteomics, RT-PCR, and Western blotting. TLM pre-treatment significantly reduced the tumor burden when combined with CFM-4.17 nanoformulation and OSM combination (TLM_CFM-F_OSM) than their respective single treatments or combination of OSM and TLM with CFM 4.17. Data from RNA sequencing and proteomics revealed that TLM_CFM-F_OSM decreased the expression of Lamin B2, STAT3, SOD, NFKB, MMP-1, TGF beta, Sox-2, and PD-L1 proteins while increasing the expression of AMPK proteins, which was also confirmed by RT-PCR, proteomics, and Western blotting. According to our findings, the TLM_CFM-F_OSM combination has a superior anti-cancer effect in the treatment of NSCLC by affecting multiple resistant markers that regulate mitochondrial homeostasis, inflammation, oxidative stress, and apoptosis.

show abstract

Section: Introductionsupporting

confidence: 86%

Combined Transcriptomic and Proteomic Profiling to Unravel Osimertinib, CARP-1 Functional Mimetic (CFM 4.17) Formulation and Telmisartan Combo Treatment in NSCLC Tumor Xenografts

et al. 2022

View full text Add to dashboard Cite

show abstract

“…Intriguingly, some of the most frequent faulty proteins that we identified are already being investigated for their therapeutic potential, which endorses the value of the proposed GR-based approach for drug target prioritisation (see Additional file 1 : S4). For example, Fienberg and colleagues are trying to selectively inhibit the domains of the ACE protein to treat fibrosis and hypertension ( Fienberg et al 2018 ); Ding et al are developing dual inhibitors of EGFR and PI3K α as an approach against tumours ( Ding et al 2018 ); similarly, early-phase trials suggest that therapies targeting the PI3K/AKT/mTOR pathway can be used in patients with advanced cancers ( Janku et al 2013 ). Finally, it has been shown that directly targeting STAT3 with piperlongumine has positive and potent effects against breast cancer ( Bharadwaj et al 2014 ).…”

Section: Resultsmentioning

confidence: 99%

Geometric characterisation of disease modules

2018

View full text Add to dashboard Cite

There is an increasing accumulation of evidence supporting the existence of a hyperbolic geometry underlying the network representation of complex systems. In particular, it has been shown that the latent geometry of the human protein network (hPIN) captures biologically relevant information, leading to a meaningful visual representation of protein-protein interactions and translating challenging systems biology problems into measuring distances between proteins. Moreover, proteins can efficiently communicate with each other, without global knowledge of the hPIN structure, via a greedy routing (GR) process in which hyperbolic distances guide biological signals from source to target proteins.It is thanks to this effective information routing throughout the hPIN that the cell operates, communicates with other cells and reacts to environmental changes. As a result, the malfunction of one or a few members of this intricate system can disturb its dynamics and derive in disease phenotypes. In fact, it is known that the proteins associated with a single disease agglomerate non-randomly in the same region of the hPIN, forming one or several connected components known as the disease module (DM).Here, we present a geometric characterisation of DMs. First, we found that DM positions on the two-dimensional hyperbolic plane reflect their fragmentation and functional heterogeneity, rendering an informative picture of the cellular processes that the disease is affecting. Second, we used a distance-based dissimilarity measure to cluster DMs with shared clinical features. Finally, we took advantage of the GR strategy to study how defective proteins affect the transduction of signals throughout the hPIN.Electronic supplementary materialThe online version of this article (10.1007/s41109-018-0066-3) contains supplementary material, which is available to authorized users.

show abstract

“…DHW-208 could bind to mTOR complex and the protein-ligand complex was stabilized by H-bonding and hydrophobic interactions. In our previous study, we found that DHW-208 showed significant kinase inhibitory activity against four main subunits of PI3K 31 . Presently, DHW-208 also showed strong inhibitory activity against mTOR kinase.…”

Section: Dhw-208 Inhibits the Pi3k/akt/mtor-signaling Pathway In Breamentioning

confidence: 93%

“…Moreover, some 4-aminoquinazoline derivatives have ever been reported as PI3K inhibitors 30 . Previously, we had designed and synthesized a series of 4-aminoquinazoline derivatives targeting the PI3K/AKT/mTOR-signaling pathway 31 . Among them, 2,4-difluoro-N-(5-(4-((1-(2-hydroxyethyl)-1H-pyrazol-4-yl)amino)quinazolin-6-yl)-2-methoxypyridin-3-yl)benzenesulfonamide (DHW-208) ( Fig.…”

Section: Introductionmentioning

confidence: 99%

A novel 4-aminoquinazoline derivative, DHW-208, suppresses the growth of human breast cancer cells by targeting the PI3K/AKT/mTOR pathway

et al. 2020

View full text Add to dashboard Cite

Breast cancer is one of the most frequent cancers among women worldwide. However, there is still no effective therapeutic strategy for advanced breast cancer that has metastasized. Aberrant activation of the PI3K/AKT/mTOR pathway is an essential step for the growth of human breast cancers. In our previous study, we designed and synthesized DHW-208 (2,4-difluoro-N-(5-(4-((1-(2-hydroxyethyl)-1H-pyrazol-4-yl)amino)quinazolin-6-yl)-2methoxypyridin-3-yl)benzenesulfonamide) as a novel pan-PI3K inhibitor. This study aimed to assess the therapeutic efficacy of DHW-208 in breast cancer and investigate its underlying mechanism. We found that DHW-208 inhibited the growth, proliferation, migration, and invasion of breast cancer cells. Moreover, DHW-208 induced breast cancer cell apoptosis via the mitochondrial pathway and induced G0/G1 cell-cycle arrest. In vitro results show that DHW-208 is a dual inhibitor of PI3K and mTOR, and suppress the growth of human breast cancer cells by targeting the PI3K/AKT/ mTOR pathway. Consistent with the in vitro results, in vivo studies demonstrated that DHW-208 elicits an antitumor effect by inhibiting the PI3K/AKT/mTOR-signaling pathway with a high degree of safety in breast cancer. Above all, we report for the first time that DHW-208 suppressed the growth of human breast cancer cells by inhibiting the PI3K/AKT/ mTOR-signaling pathway both in vivo and in vitro. Our study may provide evidence for the use of DHW-208 as an effective, novel therapeutic candidate for the treatment of human breast cancers in clinical trials.

show abstract

Design, synthesis and biological evaluation of novel 4-aminoquinazolines as dual target inhibitors of EGFR-PI3Kα

Cited by 18 publications

References 20 publications

Combined Transcriptomic and Proteomic Profiling to Unravel Osimertinib, CARP-1 Functional Mimetic (CFM 4.17) Formulation and Telmisartan Combo Treatment in NSCLC Tumor Xenografts

Combined Transcriptomic and Proteomic Profiling to Unravel Osimertinib, CARP-1 Functional Mimetic (CFM 4.17) Formulation and Telmisartan Combo Treatment in NSCLC Tumor Xenografts

Geometric characterisation of disease modules

A novel 4-aminoquinazoline derivative, DHW-208, suppresses the growth of human breast cancer cells by targeting the PI3K/AKT/mTOR pathway

Contact Info

Product

Resources

About