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Hydrazone is a bioactive pharmacophore that can be used to design antitumor agents. We synthesised a series of hydrazones (compounds 4–24) incorporating a 4-methylsulfonylbenzene scaffold and analysed their potential antitumor activity. Compounds 6, 9, 16, and 20 had the most antitumor activity with a positive cytotoxic effect (PCE) of 52/59, 27/59, 59/59, and 59/59, respectively, while compounds 5, 10, 14, 15, 18, and 19 had a moderate antitumor activity with a PCE of 11/59–14/59. Compound 20 was the most active and had a mean 50% cell growth inhibition (GI50) of 0.26 µM. Compounds 9 and 20 showed the highest inhibitory activity against COX-2, with a half-maximal inhibitory concentration (IC50) of 2.97 and 6.94 μM, respectively. Compounds 16 and 20 significantly inhibited EGFR (IC50 = 0.2 and 0.19 μM, respectively) and HER2 (IC50 = 0.13 and 0.07 μM, respectively). Molecular docking studies of derivatives 9, 16, and 20 into the binding sites of COX-2, EGFR, and HER2 were carried out to explore the interaction mode and the structural requirements for antitumor activity.

Hydrazone is a bioactive pharmacophore that can be used to design antitumor agents. We synthesised a series of hydrazones (compounds 4–24) incorporating a 4-methylsulfonylbenzene scaffold and analysed their potential antitumor activity. Compounds 6, 9, 16, and 20 had the most antitumor activity with a positive cytotoxic effect (PCE) of 52/59, 27/59, 59/59, and 59/59, respectively, while compounds 5, 10, 14, 15, 18, and 19 had a moderate antitumor activity with a PCE of 11/59–14/59. Compound 20 was the most active and had a mean 50% cell growth inhibition (GI50) of 0.26 µM. Compounds 9 and 20 showed the highest inhibitory activity against COX-2, with a half-maximal inhibitory concentration (IC50) of 2.97 and 6.94 μM, respectively. Compounds 16 and 20 significantly inhibited EGFR (IC50 = 0.2 and 0.19 μM, respectively) and HER2 (IC50 = 0.13 and 0.07 μM, respectively). Molecular docking studies of derivatives 9, 16, and 20 into the binding sites of COX-2, EGFR, and HER2 were carried out to explore the interaction mode and the structural requirements for antitumor activity. Compound 20 (MG_MID = 0.26 µM) is nearly 65-fold more potent than celecoxib (MG_MID = 17.5 µM), 3-fold more potent than 5-Fu (MG_MID = 0.90 µM), 30-fold more potent than erlotinib (MG_MID = 7.68 µM), and 9-fold more potent than gefitinib (MG_MID = 2.1 µM) and sorafenib (MG_MID = 2.33 µM). [ABSTRACT FROM AUTHOR]

Human epidermal growth factor receptor-2 (HER2)is responsible for 20% of the breast cancer cases which mainly affect the female population is due to over expression of which is the dominant tyrosine kinase receptor. In general, 9-anilinoacridine derivativesplay an important role for antitumor due to their DNA-intercalating properties. Some novel 9-anilinoacridinessubstituted with chalcone moiety(1a-z) were designed and their HER2enzyme (PDB id-3PP0) inhibition activity was performed by molecular docking studies by using Glide module of Schrodinger suit 2019-4. Glide module of the Schrodinger suit, was used to perform docking studies and Prime-MMGBSA module was used for free binding energy calculations. Based on GLIDE score, we can determine the binding affinity of ligands (1az) towards HER2. Theinhibitory activity of ligands against HER2 was mainly due to the strong hydrophobic and hydrogen bonding interactions. Almost all the compounds 1a-z, have good binding affinity with Glide scores in the range of -5.4 to -9.69 when compared with the standard drugs CK0403(-4.105) and Tamoxifen (-3.78). From the results ofMM-GBSA binding calculations revealed that most of the potent inhibitors are more stable. From the results of in-silico studies, provide the strong evidence for valuable ligands fromchalcone substituted 9-anilinoacridines as potential HER2 inhibitors and the compounds, 1m,v,r,h,d,j with significant Glide scores may produce significant antibreast cancer activity for further development. [ABSTRACT FROM AUTHOR]

The human epidermal growth factor receptor 2 (HER2) is a member of the erbB class of tyrosine kinase receptors. These proteins are normally expressed at the surface of healthy cells and play critical roles in the signal transduction cascade in a myriad of biochemical pathways responsible for cell growth and differentiation. However, it is widely known that amplification and subsequent overexpression of the HER2 encoding oncogene results in unregulated cell proliferation in an aggressive form of breast cancer known as HER2-positive breast cancer. Existing therapies such as trastuzumab (Herceptin®) and lapatinib (Tyverb/Tykerb®), a monoclonal antibody inhibitor and a dual EGFR/HER2 kinase inhibitor, respectively, are currently used in the treatment of HER2-positive cancers, although issues with high recurrence and acquired resistance still remain. Small molecule tyrosine kinase inhibitors provide attractive therapeutic targets, as they are able to block cell signaling associated with many of the proposed mechanisms for HER2 resistance. In this regard we aim to present a review on the available HER2 tyrosine kinase inhibitors, as well as those currently in development. The use of tyrosine kinase inhibitors as sequential or combinatorial therapeutic strategies with other HER family inhibitors is also discussed.

Uveal melanoma (UM) is the principal type of intraocular malignancy in adults. Up to 50% of UM patients develop metastatic disease with very poor survival. There are few drugs available to treat the primary or metastatic UM. This study was undertaken to evaluate the anti-cancer effect of lapatinib and corroborate the potential of HER2 inhibition in the treatment of UM. The anti-UM activity of lapatinib was assessed using cell viability, cell death and cell cycle analysis, and its anti-metastatic actions were evaluated using would healing, invasion and colony formation assays. Immunoblotting was used to substantiate the actions of lapatinib on apoptotic and HER2 signaling. The anti-UM activity of lapatinib was further evaluated in a UM xenograft mouse model. Lapatinib decreased the viability of four UM cell lines (IC 50 : 3.67-6.53 µM). The antiproliferative activity of lapatinib was corroborated in three primary cell lines isolated from UM patient tumors. In UM cell lines, lapatinib promoted apoptosis and cell cycle arrest, and strongly inhibited cell migration, invasion and reproductive cell growth. Lapatinib dysregulated HER2-AKT/ERK/PI3K signalling leading to the altered expression of apoptotic factors and cell cycle mediators in UM cell lines. Importantly, lapatinib suppressed tumourigenesis in mice carrying UM cell xenografts. Together the present findings are consistent with the assertion that HER2 is a viable therapeutic target in UM. Lapatinib is active in primary and metastatic UM as a clinically approved HER2 inhibitor. The activity of lapatinib in UM patients could be evaluated in future clinical trials., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Around 70% of breast cancers express the estrogen receptor α (ERα) and depend on estrogen for growth, survival and disease progression. The presence of hormone sensitivity is usually associated with a favorable prognosis. Use of adjuvant anti-endocrine therapy has significantly decreased breast cancer mortality in patients with early-stage disease, and anti-endocrine therapy also plays a central role in the treatment of advanced stages. However a subset of hormone receptor-positive breast cancers do not benefit from anti-endocrine therapy, and nearly all hormone receptor-positive metastatic breast cancers ultimately develop resistance to anti-hormonal therapies. Despite new insights into mechanisms of anti-endocrine therapy resistance, e.g., crosstalk between ERα and Her2/neu, the management of advanced hormone-receptor-positive breast cancers that are resistant to anti-endocrine agents remains a significant challenge. In the present study, we demonstrate that the proteasome inhibitor Bortezomib strongly inhibits ERα and HER2/neu expression, increases expression of cyclin-dependent kinase inhibitors, inhibits expression of multiple genes associated with poor prognosis in ERα+ breast cancer patients and induces cell death in ER+ breast cancer cells in both the presence and absence of functional p53. Although Bortezomib increased the levels of p53 and increased the expression of pro-apoptotic target genes in ERα+ breast cancer cells harboring wild-type p53, Bortezomib also exerts anti-tumoral effects on ERα+ breast cancer cells through suppression of ERα expression and inhibition of PI3K/Akt/mammalian target of rapamycin (mTOR) and ERK signaling independently of functional p53. These findings suggest that Bortezomib might have the potential to improve the management of anti-endocrine therapy resistant ERα+ breast cancers independently of their p53 status. [ABSTRACT FROM AUTHOR]

The human epidermal growth factor receptor 2 (HER2) is a member of the erbB class of tyrosine kinase receptors. These proteins are normally expressed at the surface of healthy cells and play critical roles in the signal transduction cascade in a myriad of biochemical pathways responsible for cell growth and differentiation. However, it is widely known that amplification and subsequent overexpression of the HER2 encoding oncogene results in unregulated cell proliferation in an aggressive form of breast cancer known as HER2-positive breast cancer. Existing therapies such as trastuzumab (Herceptin®) and lapatinib (Tyverb/Tykerb®), a monoclonal antibody inhibitor and a dual EGFR/HER2 kinase inhibitor, respectively, are currently used in the treatment of HER2-positive cancers, although issues with high recurrence and acquired resistance still remain. Small molecule tyrosine kinase inhibitors provide attractive therapeutic targets, as they are able to block cell signaling associated with many of the proposed mechanisms for HER2 resistance. In this regard we aim to present a review on the available HER2 tyrosine kinase inhibitors, as well as those currently in development. The use of tyrosine kinase inhibitors as sequential or combinatorial therapeutic strategies with other HER family inhibitors is also discussed. [ABSTRACT FROM AUTHOR]

Background: Breast cancer is one of the malignant tumours which mainly affect the female population. 20% of the cases of breast cancer are due to the over-expression of Human epidermal growth factor receptor-2 (HER2), which is the dominant tyrosine kinase receptor. In general, 9-anilinoacridine derivatives play an important role in antitumor activity due to their DNA-intercalating properties., Objective: Some novel 9-anilinoacridines substituted with pyrazole moiety (1a-z) were designed and their HER2enzyme (PDB id-3PP0) inhibition activity was performed by molecular docking studies using the Glide module of Schrodinger suite 2019-4., Methods: Glide module of the Schrodinger suite was used to perform docking studies; qikprop module was used for in-silico ADMET screening and the Prime-MMGBSA module was used for free binding energy calculations. Based on GLIDE scoring functions, we can determine the binding affinity of ligands (1a-z) towards HER2., Results: The inhibitory activity of ligands against HER2 was mainly due to the strong hydrophobic and hydrogen bonding interactions. Almost all the compounds 1a-z exhibited a good binding affinity with Glide scores in the range of -4.9 to -9.75, when compared with the standard drugs CK0403 (-4.105) and Tamoxifen (-3.78). From the results of in-silico ADMET properties, it was evident that most of the compounds fell within the recommended values. MM-GBSA binding calculations of the most potent inhibitors were found to be more favourable., Conclusion: The results of in-silico studies provide strong evidence for the potential of valuable ligands in pyrazole substituted 9-anilinoacridines as HER2 inhibitors, and the compounds, 1v,s,r,d,a,o with significant Glide scores may produce significant anti-breast cancer activity., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)