Gastric cancers are caused primarily due to the activation and amplification of the EGFR or HER2 kinases resulting in cell proliferation,adhesion,angiogenesis,and metastasis.Conventional therapies are ineffective due ...Gastric cancers are caused primarily due to the activation and amplification of the EGFR or HER2 kinases resulting in cell proliferation,adhesion,angiogenesis,and metastasis.Conventional therapies are ineffective due to the intra-tumoral heterogeneity and concomitant genetic mutations.Hence,dual inhibition strategies are recommended to increase potency and reduce cytotoxicity.In this study,we have conducted computational high-throughput screening of the ChemBridge library followed by in vitro assays and identified novel selective inhibitors that have a dual impediment of EGFR/HER2 kinase activities.Diversity-based High-throughput Virtual Screening(D-HTVS)was used to screen the whole ChemBridge small molecular library against EGFR and HER2.The atomistic molecular dynamic simulation was conducted to understand the dynamics and stability of the protein-ligand complexes.EGFR/HER2 kinase enzymes,KATOIII,and Snu-5 cells were used for in vitro validations.The atomistic Molecular Dynamics simulations followed by solvent-based Gibbs binding free energy calculation of top molecules,identified compound C3(5-(4-oxo-4H-3,1-benzoxazin-2-yl)-2-[3-(4-oxo-4H-3,1-benzoxazin-2-yl)phenyl]-1H-isoindole-1,3(2H)-dione)to have a good affinity for both EGFR and HER2.The predicted compound,C3,was promising with better binding energy,good binding pose,and optimum interactions with the EGFR and HER2 residues.C3 inhibited EGFR and HER2 kinases with IC50 values of 37.24 and 45.83 nM,respectively.The GI50 values of C3 to inhibit KATOIII and Snu-5 cells were 84.76 and 48.26 nM,respectively.Based on these findings,we conclude that the identified compound C3 showed a conceivable dual inhibitory activity on EGFR/HER2 kinase,and therefore can be considered as a plausible lead-like molecule for treating gastric cancers with minimal side effects,though testing in higher models with pharmacokinetic approach is required.展开更多
Introduction: Members of the Human Epidermal Receptor [HER] family of receptor tyrosine kinases, such as HER2 and EGFR proteins are overexpressed in several epithelial malignancies and serve as effective therapeutic t...Introduction: Members of the Human Epidermal Receptor [HER] family of receptor tyrosine kinases, such as HER2 and EGFR proteins are overexpressed in several epithelial malignancies and serve as effective therapeutic targets in cancer management. However, their role in prostate cancer development has been sparingly explored and with contrasting findings. Notably their relationship with prostate cancers cases seen in Sub-Saharan Africa is yet to be explored. Design: A retrospective study involving histologically diagnosed cases of adenocarcinomas of the prostate. Cases were classed according to the WHO/ISUP Gleason Prognostic groups [G1 - G5]. Immunohistochemical analysis was performed using monoclonal antibodies for HER2 and EGFR, while in situ hybridization employed DNA probes for the corresponding genes. Scores of +2 and +3 were regarded as positive for both antibodies, while a target gene: centromere ratio of >2 was set as the threshold for amplification. Results: A total of 44 cases were included in the study. The acinar type was the commonest morphologically, with Gleason group 5 [Gleason scores 8 - 10] accounting for close to half of the cases [47.7%]. The HER2 antibody stained negatively in the majority of cases [93.2%], being positive in only 3 [6.8%] of cases seen. High level expression of EGFR [+2/+3] was observed in 25% of cases, low level expression was identified in 6 [13.6%] cases. All HER2 positive malignancies displayed overexpression of EGFR. In situ-hybridization revealed the absence of high level amplification for both HER2 and EGFR, while polysomy was not detected in any of the cases. Conclusion: The overexpression of EGFR in prostate cancers has been demonstrated in a native African population, affirming its suitability for targeted therapy. Overexpression of HER2 in prostate cancer is inconstant, and amplification of the HER2 gene is less frequent than as compared to malignancies of the Breast and Ovary. There’s a need for a standardized protocol for assessing HER2 in prostate cancer.展开更多
文摘Gastric cancers are caused primarily due to the activation and amplification of the EGFR or HER2 kinases resulting in cell proliferation,adhesion,angiogenesis,and metastasis.Conventional therapies are ineffective due to the intra-tumoral heterogeneity and concomitant genetic mutations.Hence,dual inhibition strategies are recommended to increase potency and reduce cytotoxicity.In this study,we have conducted computational high-throughput screening of the ChemBridge library followed by in vitro assays and identified novel selective inhibitors that have a dual impediment of EGFR/HER2 kinase activities.Diversity-based High-throughput Virtual Screening(D-HTVS)was used to screen the whole ChemBridge small molecular library against EGFR and HER2.The atomistic molecular dynamic simulation was conducted to understand the dynamics and stability of the protein-ligand complexes.EGFR/HER2 kinase enzymes,KATOIII,and Snu-5 cells were used for in vitro validations.The atomistic Molecular Dynamics simulations followed by solvent-based Gibbs binding free energy calculation of top molecules,identified compound C3(5-(4-oxo-4H-3,1-benzoxazin-2-yl)-2-[3-(4-oxo-4H-3,1-benzoxazin-2-yl)phenyl]-1H-isoindole-1,3(2H)-dione)to have a good affinity for both EGFR and HER2.The predicted compound,C3,was promising with better binding energy,good binding pose,and optimum interactions with the EGFR and HER2 residues.C3 inhibited EGFR and HER2 kinases with IC50 values of 37.24 and 45.83 nM,respectively.The GI50 values of C3 to inhibit KATOIII and Snu-5 cells were 84.76 and 48.26 nM,respectively.Based on these findings,we conclude that the identified compound C3 showed a conceivable dual inhibitory activity on EGFR/HER2 kinase,and therefore can be considered as a plausible lead-like molecule for treating gastric cancers with minimal side effects,though testing in higher models with pharmacokinetic approach is required.
文摘Introduction: Members of the Human Epidermal Receptor [HER] family of receptor tyrosine kinases, such as HER2 and EGFR proteins are overexpressed in several epithelial malignancies and serve as effective therapeutic targets in cancer management. However, their role in prostate cancer development has been sparingly explored and with contrasting findings. Notably their relationship with prostate cancers cases seen in Sub-Saharan Africa is yet to be explored. Design: A retrospective study involving histologically diagnosed cases of adenocarcinomas of the prostate. Cases were classed according to the WHO/ISUP Gleason Prognostic groups [G1 - G5]. Immunohistochemical analysis was performed using monoclonal antibodies for HER2 and EGFR, while in situ hybridization employed DNA probes for the corresponding genes. Scores of +2 and +3 were regarded as positive for both antibodies, while a target gene: centromere ratio of >2 was set as the threshold for amplification. Results: A total of 44 cases were included in the study. The acinar type was the commonest morphologically, with Gleason group 5 [Gleason scores 8 - 10] accounting for close to half of the cases [47.7%]. The HER2 antibody stained negatively in the majority of cases [93.2%], being positive in only 3 [6.8%] of cases seen. High level expression of EGFR [+2/+3] was observed in 25% of cases, low level expression was identified in 6 [13.6%] cases. All HER2 positive malignancies displayed overexpression of EGFR. In situ-hybridization revealed the absence of high level amplification for both HER2 and EGFR, while polysomy was not detected in any of the cases. Conclusion: The overexpression of EGFR in prostate cancers has been demonstrated in a native African population, affirming its suitability for targeted therapy. Overexpression of HER2 in prostate cancer is inconstant, and amplification of the HER2 gene is less frequent than as compared to malignancies of the Breast and Ovary. There’s a need for a standardized protocol for assessing HER2 in prostate cancer.
