Exploring receptor tyrosine kinases-inhibitors in Cancer treatments

Metibemu, Damilohun Samuel; Akinloye, Oluyemi; Akamo, Adio J.; Ojo, D. A.; Okeowo, O. Tolulope; Omotuyi, Idowu Olaposi

doi:10.1186/s43042-019-0035-0

Cited by 74 publications

(44 citation statements)

References 181 publications

(189 reference statements)

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“…Therefore, we selected two proteins from the receptor tyrosine kinases family. They contain an extracellular ligand-binding region, transmembrane domain, and an intracellular region with a tyrosine kinase domain 45 . Binding of a specific ligand to an extracellular region induces phosphorylation process, leading to structural transformation within the kinase domain.…”

Section: Resultsmentioning

confidence: 99%

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Transformer neural network for protein-specific de novo drug generation as a machine translation problem

Grechishnikova

2021

Sci Rep

138

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Drug discovery for a protein target is a very laborious, long and costly process. Machine learning approaches and, in particular, deep generative networks can substantially reduce development time and costs. However, the majority of methods imply prior knowledge of protein binders, their physicochemical characteristics or the three-dimensional structure of the protein. The method proposed in this work generates novel molecules with predicted ability to bind a target protein by relying on its amino acid sequence only. We consider target-specific de novo drug design as a translational problem between the amino acid “language” and simplified molecular input line entry system representation of the molecule. To tackle this problem, we apply Transformer neural network architecture, a state-of-the-art approach in sequence transduction tasks. Transformer is based on a self-attention technique, which allows the capture of long-range dependencies between items in sequence. The model generates realistic diverse compounds with structural novelty. The computed physicochemical properties and common metrics used in drug discovery fall within the plausible drug-like range of values.

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Section: Resultsmentioning

confidence: 99%

“…This results in activation of a corresponding signal pathway. The vast majority of reported kinase inhibitors binds to the catalytic domain essential for kinase activity 45 . The first selected protein is the Insulin-like growth factor 1 receptor (IGF-1R).…”

Section: Resultsmentioning

confidence: 99%

Transformer neural network for protein-specific de novo drug generation as a machine translation problem

Grechishnikova

2021

Sci Rep

138

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“…Thus, RTKs and their ligands were proven to be promising targets in the treatment of GBM. Among the several receptors belonging to the RTK group in human glioma, the signaling pathways such as EGFR and VEGF receptor mutations have played a significant role in GBM described below in detail [ 52 ].…”

Section: Receptors Tyrosine Kinase (Rtk) and Their Inhibitors Of Imentioning

confidence: 99%

“…Various active components prevent the EGFR activity, and its ligands have been under progress since the starting of this era. Small molecular EGFR protein tyrosine kinase inhibitors (EGFR–TKIs) have become the most innovative active component in anti-cancer management [ 52 ]. EGFR–TKIs are a 4-anilinoquinazoline structure that could covalently link with the ATP binding site of the RTK to procedure the dynamic conformation.…”

Section: Molecular Drug Therapy Targets and Its Clinical Profile Omentioning

confidence: 99%

Nanodelivery Systems Targeting Epidermal Growth Factor Receptors for Glioma Management

et al. 2020

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A paradigm shift in treating the most aggressive and malignant form of glioma is continuously evolving; however, these strategies do not provide a better life and survival index. Currently, neurosurgical debulking, radiotherapy, and chemotherapy are the treatment options available for glioma, but these are non-specific in action. Patients invariably develop resistance to these therapies, leading to recurrence and death. Receptor Tyrosine Kinases (RTKs) are among the most common cell surface proteins in glioma and play a significant role in malignant progression; thus, these are currently being explored as therapeutic targets. RTKs belong to the family of cell surface receptors that are activated by ligands which in turn activates two major downstream signaling pathways via Rapidly Accelerating Sarcoma/mitogen activated protein kinase/extracellular-signal-regulated kinase (Ras/MAPK/ERK) and phosphatidylinositol 3-kinase/a serine/threonine protein kinase/mammalian target of rapamycin (PI3K/AKT/mTOR). These pathways are critically involved in regulating cell proliferation, invasion, metabolism, autophagy, and apoptosis. Dysregulation in these pathways results in uncontrolled glioma cell proliferation, invasion, angiogenesis, and cancer progression. Thus, RTK pathways are considered a potential target in glioma management. This review summarizes the possible risk factors involved in the growth of glioblastoma (GBM). The role of RTKs inhibitors (TKIs) and the intracellular signaling pathways involved, small molecules under clinical trials, and the updates were discussed. We have also compiled information on the outcomes from the various endothelial growth factor receptor (EGFR)–TKIs-based nanoformulations from the preclinical and clinical points of view. Aided by an extensive literature search, we propose the challenges and potential opportunities for future research on EGFR–TKIs-based nanodelivery systems.

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“…These receptors have the same protein structure containing extracellular domain for binding with the ligand, transmembrane helix in addition to the TK cytoplasmic domain. [ 13,14 ]…”

Section: Introductionmentioning

confidence: 99%

Dual EGFR/VEGFR2 inhibitors and apoptosis inducers: Synthesis and antitumor activity of novel pyrazoline derivatives

Alkamaly

Altwaijry

Sabour

et al. 2020

Archiv der Pharmazie

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Novel derivatives of the pyrazoline scaffold were synthesized and investigated for their cytotoxicity against prostate (PC‐3), hepatocellular (HepG2), and breast (MDA‐MB‐231) carcinoma cells. The most active compounds, 4a, 4b, 5b, and 7c, revealed significant and broad‐spectrum anticancer activities with IC50 values of 1.30–7.18 μM in comparison with doxorubicin (IC50 = 5.12–7.33 μM). Additionally, they exhibited lower cytotoxicity against normal WI‐38 cells, indicating their high safety profiles. Aiming to enlighten the inhibitory potential on receptor tyrosine kinases (RTKs), compounds 4a, 4b, 5b, and 7c were assessed for their activities against four different RTKs (EGFR, FGFR2, HER2, and VEGFR2) and their apoptotic potencies on PC‐3 cells. The results revealed that compounds 5b and 7c are potent dual EGFR and VEGFR2 inhibitors (IC50 = 0.21 and 0.23 μM, respectively, against EGFR; 0.22 and 0.21 μM, respectively, against VEGFR2), whereas they displayed moderate inhibitory activities against HER2 and FGFR2. Besides, compounds 4a, 4b, 5b, and 7c prompted apoptosis via the upregulation of Bax, p53, and caspase‐3, together with the downregulation of the levels of Bcl‐2. Also, it was found that compounds 5b and 7c are more potent as apoptosis inducers than the other tested derivatives. Furthermore, molecular docking analyses of compounds 4a, 4b, 5b, and 7c in the EGFR and VEGFR ATP binding sites were performed, to confirm the in vitro assays.

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Exploring receptor tyrosine kinases-inhibitors in Cancer treatments

Cited by 74 publications

References 181 publications

Transformer neural network for protein-specific de novo drug generation as a machine translation problem

Transformer neural network for protein-specific de novo drug generation as a machine translation problem

Nanodelivery Systems Targeting Epidermal Growth Factor Receptors for Glioma Management

Dual EGFR/VEGFR2 inhibitors and apoptosis inducers: Synthesis and antitumor activity of novel pyrazoline derivatives

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