Emerging Importance of Tyrosine Kinase Inhibitors against Cancer: Quo Vadis to Cure?

Mongre, Raj Kumar; Mishra, Chandra Bhushan; Shukla, Arvind Kumar; Prakash, Amresh; Jung, Samil; Ashraf-Uz-Zaman, Md

doi:10.3390/ijms222111659

Cited by 21 publications

(15 citation statements)

References 117 publications

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“…The regimen of cancer treatment is greatly modified by increasing the knowledge of molecular and tumour biology 6 . Noticeably, the selectivity of anticancer approaches has a low margin 7 . So, it is a serious concern to develop a new strategy of treating cancer that provides a high selectivity margin.…”

Section: Introductionmentioning

confidence: 99%

Discovery of new 1H-pyrazolo[3,4-d]pyrimidine derivatives as anticancer agents targeting EGFR^WT and EGFR^T790M

Gaber

Sobhy

Turky

et al. 2022

Journal of Enzyme Inhibition and Medicinal Chemistry

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New 1 H -pyrazolo[3,4-d]pyrimidine derivatives were designed and synthesised to act as epidermal growth factor receptor inhibitors (EGFRIs). The synthesised derivatives were assessed for their in vitro anti-proliferative activities against A549 and HCT-116 cancer cells. Compounds 8, 10, 12a, and 12b showed potent anti-proliferative activities. Compound 12b was the most promising member with IC 50 values of 8.21 and 19.56 µM against A549 and HCT-116, respectively. Compounds 8, 10, 12a, and 12b were evaluated for their kinase inhibitory activities against wild EGFR (EGFR WT ). Compound 12b was the most potent member showing an IC 50 value of 0.016 µM. In addition, compound 12b showed noticeable activity against mutant EGFR (EGFR T790M ) (IC 50 = 0.236 µM). Flow cytometric analyses revealed that compound 12b is a good apoptotic inducer and can arrest the cell cycle at S and G2/M phases. Furthermore, it produced an 8.8-fold increase in BAX/Bcl-2 ratio. Molecular docking studies were carried out against EGFR WT and EGFR T790M .

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Section: Introductionmentioning

confidence: 99%

Discovery of new 1H-pyrazolo[3,4-d]pyrimidine derivatives as anticancer agents targeting EGFR^WT and EGFR^T790M

Gaber

Sobhy

Turky

et al. 2022

Journal of Enzyme Inhibition and Medicinal Chemistry

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“…We downloaded IC 50 concentration Z scores from GDSC2 (Genomics of Drug Sensitivity in Cancer, dataset2) database (Iorio et al, 2016) for antitumor drugs that target key cancer-related cellular pathways (Figure 6B). We identified 4 compounds, AZ960 (Yang et al, 2010), JAK_8517, JAK1_8709 (Mongre et al, 2021) and Ruxolitinib (Han et al, 2018), that specifically target proteins in the JAK/STAT pathway and compared their drug sensitivity to PTPRM promoter methylation status in pancreatic cancer cell lines. We observed that drug sensitivity was significantly proportional to DNA methylation levels of the PTPRM gene promoter in pancreatic cancer cell lines (rho = 0.3, P = 0.00462) (Figure 6C) suggesting that PTPRM promoter methylation profiles maybe used as a potential biomarker for clinical treatment response in pancreatic cancer patient therapy.…”

Section: Resultsmentioning

confidence: 99%

Cellular and clinical impact of Protein Phosphatase Enzyme epigenetic silencing in multiple cancer tissues

Joshi

Esteller

2022

Preprint

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Protein Phosphatase Enzymes (PPE) and protein kinases simultaneously control phosphorylation mechanisms that tightly regulate intracellular signaling pathways and stimulate cellular responses. In human malignancies, PPE and protein kinases are frequently mutated resulting in uncontrolled kinase activity and PPE suppression, leading to cell proliferation, migration and resistance to anti-cancer therapies. Cancer associated DNA hypermethylation at PPE promoters gives rise to transcriptional silencing (epimutations) and is a hallmark of cancer. Despite recent advances in sequencing technologies, data availability and computational capabilities, only a fraction of PPE have been reported as transcriptionally inactive as a consequence of epimutations. Using the Infinium HumanMethylation450 BeadChip, we compared DNA methylation profiles from 705 cancer patients across 5 major tissues and 3 cancer cell models against a cohort of healthy controls. Here, we report epimutations in PPEIP genes are a frequent occurrence in the cancer genome and manifest independent of transcriptional activity. We observed that different tumors have varying susceptibility to epimutations and identify specific cellular signalling networks that are primarily affected by epimutations. Additionally, RNA-seq analysis showed the negative impact of epimutations on most (not all) Protein Tyrosine Phosphatase transcription. Finally, we detected novel clinical biomarkers that inform on patient mortality and anti-cancer treatment sensitivity. We propose that DNA hypermethylation marks at PPEIP frequently contribute to the pathogenesis of malignancies and in the precision medicine space, hold promise as biomarkers to inform on clinical features such as patient survival and therapeutic response.

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“…Dysfunctional RTKs result in developmental problems leading to diseases, including diabetes, atherosclerosis, and cancer. For example, RTKs are well-studied and targeted therapeutics for cancer [14] and diabetes [15]. Functional characteristics of organelles and cells are determined by the protein compositions at different physiological states [4].…”

Section: Membrane Proteins: Role In Diseases and Potential As Biomarkersmentioning

confidence: 99%

Aptamers Targeting Membrane Proteins for Sensor and Diagnostic Applications

et al. 2023

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Many biological processes (physiological or pathological) are relevant to membrane proteins (MPs), which account for almost 30% of the total of human proteins. As such, MPs can serve as predictive molecular biomarkers for disease diagnosis and prognosis. Indeed, cell surface MPs are an important class of attractive targets of the currently prescribed therapeutic drugs and diagnostic molecules used in disease detection. The oligonucleotides known as aptamers can be selected against a particular target with high affinity and selectivity by iterative rounds of in vitro library evolution, known as Systematic Evolution of Ligands by EXponential Enrichment (SELEX). As an alternative to antibodies, aptamers offer unique features like thermal stability, low-cost, reuse, ease of chemical modification, and compatibility with various detection techniques. Particularly, immobilized-aptamer sensing platforms have been under investigation for diagnostics and have demonstrated significant value compared to other analytical techniques. These “aptasensors” can be classified into several types based on their working principle, which are commonly electrochemical, optical, or mass-sensitive. In this review, we review the studies on aptamer-based MP-sensing technologies for diagnostic applications and have included new methodological variations undertaken in recent years.

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Emerging Importance of Tyrosine Kinase Inhibitors against Cancer: Quo Vadis to Cure?

Cited by 21 publications

References 117 publications

Discovery of new 1H-pyrazolo[3,4-d]pyrimidine derivatives as anticancer agents targeting EGFR^WT and EGFR^T790M

Discovery of new 1H-pyrazolo[3,4-d]pyrimidine derivatives as anticancer agents targeting EGFR^WT and EGFR^T790M

Cellular and clinical impact of Protein Phosphatase Enzyme epigenetic silencing in multiple cancer tissues

Aptamers Targeting Membrane Proteins for Sensor and Diagnostic Applications

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Emerging Importance of Tyrosine Kinase Inhibitors against Cancer: Quo Vadis to Cure?

Cited by 21 publications

References 117 publications

Discovery of new 1H-pyrazolo[3,4-d]pyrimidine derivatives as anticancer agents targeting EGFRWT and EGFRT790M

Discovery of new 1H-pyrazolo[3,4-d]pyrimidine derivatives as anticancer agents targeting EGFRWT and EGFRT790M

Cellular and clinical impact of Protein Phosphatase Enzyme epigenetic silencing in multiple cancer tissues

Aptamers Targeting Membrane Proteins for Sensor and Diagnostic Applications

Contact Info

Product

Resources

About

Discovery of new 1H-pyrazolo[3,4-d]pyrimidine derivatives as anticancer agents targeting EGFR^WT and EGFR^T790M

Discovery of new 1H-pyrazolo[3,4-d]pyrimidine derivatives as anticancer agents targeting EGFR^WT and EGFR^T790M