Novel sulfonamide benzoquinazolinones as dual EGFR/HER2 inhibitors, apoptosis inducers and radiosensitizers

Soliman, Aiten M.; Alqahtani, Ali S.; Ghorab, Mostafa M.

doi:10.1080/14756366.2019.1609469

Cited by 53 publications

(25 citation statements)

References 44 publications

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“…Quinazolinone is a strategic scaffold that has a wide range of pharmacological activities such as antioxidant, anti-inflammatory and anticancer activities [ [20] , [21] , [22] , [23] ]. Sulfonamides, in addition to their use as antibiotics [ [24] , [25] , [26] , [27] ], have many pharmacological activities and can be used as antiviral [ 28 ], anti-inflammatory [ 29 ], antioxidant [ 30 , 31 ], and anticancer agents [ [32] , [33] , [34] , [35] ]. These versatile pharmacological activities make the two chemical classes excellent candidates for developing new multi-target agents through a slight alteration in the structure that might lead to diversity in the biological activity [ 20 , 36 , 37 ].…”

Section: Introductionmentioning

confidence: 99%

Radiomodulatory effect of a non-electrophilic NQO1 inducer identified in a screen of new 6, 8-diiodoquinazolin-4(3H)-ones carrying a sulfonamide moiety

Soliman

Karam

Mekkawy

et al. 2020

European Journal of Medicinal Chemistry

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Fifteen new quinazolinone derivatives bearing benzenesulfonamide moiety with variable acetamide tail were synthesized. The structures assigned to the products were concordant with the microanalytical and spectral data. Compounds 4–18 were screened for their ability to induce the antioxidant enzyme NAD(P)H: quinone oxidoreductase 1 (NQO1) in cells, a classical target for transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2). The 2-((6,8-diiodo-4-oxo-3-(4-sulfamoylphenyl)-3,4-dihydroquinazolin-2-yl)thio)- N -(3,4,5-trimethoxyphenyl) acetamide 15 showed the most potent NQO1 inducer activity in vitro . Compound 15 had low toxicity in mice (LD 50 = 500 mg/kg). It also reduced the damaging effects of gamma radiation, as assessed by the levels of Nrf2, NQO1, reactive oxygen species (ROS) and malondialdehyde (MDA) in liver tissues. In addition, compound 15 showed amelioration in the complete blood count of irradiated mice and enhanced survival over a period of 30 days following irradiation. Molecular docking of 15 inside the Nrf2-binding site of Kelch-like ECH associated protein 1 (Keap1), the main negative regulator of Nrf2, showed the same binding interactions as that of the co-crystallized ligand considering the binding possibilities and energy scores. These findings suggest that compound 15 could be considered as a promising antioxidant and radiomodulatory agent.

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Section: Introductionmentioning

confidence: 99%

Radiomodulatory effect of a non-electrophilic NQO1 inducer identified in a screen of new 6, 8-diiodoquinazolin-4(3H)-ones carrying a sulfonamide moiety

Soliman

Karam

Mekkawy

et al. 2020

European Journal of Medicinal Chemistry

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“…Several quinazolines have been evaluated as anticancer therapeutics in different cancer cell lines and EGFR has been identified as one of the relevant molecular targets (Khodair et al, 2019 ; Soliman et al, 2019 ). Sulphonamide benzoquinazolinones have also been reported as dual EGFR/HER2 inhibitors with micromolar IC 50 values, apoptosis inducers and radiosensitizers.…”

Section: Discussionmentioning

confidence: 99%

Identification of Quinazolinone Analogs Targeting CDK5 Kinase Activity and Glioblastoma Cell Proliferation

et al. 2020

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CDK5/p25 kinase plays a major role in neuronal functions, and is hyperactivated in several human cancers including glioblastoma and neurodegenerative pathologies such as Alzheimer's and Parkinson's. CDK5 therefore constitutes an attractive pharmacological target. Since the successful discovery and development of Roscovitine, several ATP-competitive inhibitors of CDK5 and peptide inhibitors of CDK5/p25 interface have been developed. However, these compounds suffer limitations associated with their mechanism of action and nature, thereby calling for alternative targeting strategies. To date, few allosteric inhibitors have been developed for successful targeting of protein kinases. Indeed, although this latter class of inhibitors are believed to be more selective than compounds targeting the active site, they have proven extremely difficult to identify in high throughput screens. By implementing a fluorescent biosensor that discriminates against ATP-pocket binding compounds to screen for allosteric inhibitors that target conformational activation of CDK5, we have identified a novel family of quinazolinones. Characterization of these hits and several of their derivatives revealed their inhibitory potential toward CDK5 kinase activity in vitro and to inhibit glioblastoma cell proliferation. The quinazolinone derivatives described in this study are the first small molecules reported to target CDK5 at a site other than the ATP pocket, thereby constituting attractive leads for glioblastoma therapeutics and providing therapeutic perspectives for neurodegenerative diseases. These compounds offer alternatives to conventional ATP-competitive inhibitors or peptides targeting CDK5/p25 interface with the potential of bypassing their limitations.

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“…HER2 belongs to the HER/ErbB family of receptor tyrosine kinases involved in cell proliferation and angiogenesis (105).…”

Section: Human Epidermal Growth Factor Receptor 2 (Her2)mentioning

confidence: 99%

“…HER2 belongs to the HER/ErbB family of receptor tyrosine kinases involved in cell proliferation and angiogenesis ( 105 ). The anti-tumor effect of HER2 CAR-T cells against two NSCLC cell lines, A549 and H1650, was observed in a 96-h co-culture assay ( 106 ).…”

Section: Introductionmentioning

confidence: 99%

Chimeric Antigen Receptor T-Cell Therapy in Lung Cancer: Potential and Challenges

et al. 2021

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Chimeric antigen receptor T (CAR-T) cell therapy has exhibited a substantial clinical response in hematological malignancies, including B-cell leukemia, lymphoma, and multiple myeloma. Therefore, the feasibility of using CAR-T cells to treat solid tumors is actively evaluated. Currently, multiple basic research projects and clinical trials are being conducted to treat lung cancer with CAR-T cell therapy. Although numerous advances in CAR-T cell therapy have been made in hematological tumors, the technology still entails considerable challenges in treating lung cancer, such as on−target, of−tumor toxicity, paucity of tumor-specific antigen targets, T cell exhaustion in the tumor microenvironment, and low infiltration level of immune cells into solid tumor niches, which are even more complicated than their application in hematological tumors. Thus, progress in the scientific understanding of tumor immunology and improvements in the manufacture of cell products are advancing the clinical translation of these important cellular immunotherapies. This review focused on the latest research progress of CAR-T cell therapy in lung cancer treatment and for the first time, demonstrated the underlying challenges and future engineering strategies for the clinical application of CAR-T cell therapy against lung cancer.

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Novel sulfonamide benzoquinazolinones as dual EGFR/HER2 inhibitors, apoptosis inducers and radiosensitizers

Cited by 53 publications

References 44 publications

Radiomodulatory effect of a non-electrophilic NQO1 inducer identified in a screen of new 6, 8-diiodoquinazolin-4(3H)-ones carrying a sulfonamide moiety

Radiomodulatory effect of a non-electrophilic NQO1 inducer identified in a screen of new 6, 8-diiodoquinazolin-4(3H)-ones carrying a sulfonamide moiety

Identification of Quinazolinone Analogs Targeting CDK5 Kinase Activity and Glioblastoma Cell Proliferation

Chimeric Antigen Receptor T-Cell Therapy in Lung Cancer: Potential and Challenges

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