Isatin-Hydrazones with Multiple Receptor Tyrosine Kinases (RTKs) Inhibitory Activity and In-Silico Binding Mechanism

Huda S Al-Salem,Md Arifuzzaman,A F M Motiur Rahman,Iman S Issa

doi:10.3390/app11093746

Huda S Al-Salem, Md Arifuzzaman + Show 2 more

Open Access

https://doi.org/10.3390/app11093746

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Journal: Applied sciences	Publication Date: Apr 21, 2021
Citations: 12	License type: CC BY 4.0

Affiliation: King Saud University, Yeungnam University

Abstract

Recently, we have reported a series of isatin hydrazone, two of them, namely, 3-((2,6-dichlorobenzylidene)hydrazono)indolin-2-one (1) and 3-((2-chloro-6-fluorobenzylidene)hydrazono)indolin-2-one (2) having potent cytotoxicity, showing cyclin-dependent kinases (CDK2) inhibitory activity and bearing recommended drug likeness properties. Since both compounds (1 and 2) showed inhibitory activity against CDK2, we assumed it would also have multiple receptor tyrosine kinases (RTKs) inhibitory activity. Considering those points, here, above-mentioned two isatin hydrazone 1 and 2 were synthesized using previously reported method for further investigation of their potency on RTKs (EGFR, VEGFR-2 and FLT-3) inhibitory activity. As expected, Compound 1 exhibited excellent inhibitory activity against epidermal growth factor receptor (EGFR, IC50 = 0.269 µM), vascular epidermal growth factor receptor 2 (VEGFR-2, IC50 = 0.232 µM) and FMS-like tyrosine kinase-3 (FLT-3, IC50 = 1.535 µM) tyrosine kinases. On the other hand, Compound 2 also exhibited excellent inhibitory activity against EGFR (IC50 = 0.369 µM), VEGFR-2 (IC50 = 0.266 µM) and FLT-3 (IC50 = 0.546 µM) tyrosine kinases. A molecular docking study with EGFR, VEGFR-2 and FLT-3 kinase suggested that both compounds act as type I ATP competitive inhibitors against EGFR and VEGFR-2, and type II ATP non-competitive inhibitors against FLT-3.

Highlights

IntroductionDevelopment of an excellent anticancer agents are very much essential, especially ones with potent biological activities, enzyme inhibitory activities and low/no toxicity [2,3,4,5] (Figure 1)
Cancer is a complex disease but it life threatening [1]
Regarding enzyme inhibitory activities: (i) cyclin-dependent kinases (CDKs) are considered as a vital feature, inciting various key transitions in the cell cycle for cancer cells, in addition to instructing apoptosis, transcription and exocytosis; (ii) the epidermal growth factor receptor (EGFR) [6] kinase enzyme promote overexpression, and overexpression of certain proteins may play a role in various cancer development [7,8,9,10,11,12,13,14,15]; (iii) the vascular endothelial growth factor receptor 2 (VEGFR-2) [16,17] is highly expressed in tumor-associated endothelial cells, where it modulates tumor-promoting angiogenesis, and it is found on the surface of tumor cells [18]; (iv) FMS-like tyrosine kinase-3 (FLT-3) is a protein found in humans and is encoded by the FLT-3 gene [19,20,21]

Summary

Introduction

Development of an excellent anticancer agents are very much essential, especially ones with potent biological activities, enzyme inhibitory activities and low/no toxicity [2,3,4,5] (Figure 1). Mutations of the FLT-3 receptor can lead to the development of leukemia, a cancer of bone marrow hematopoietic progenitors [22,23,24,25]. The development of a cancer may be delayed or cured by inhibition of those kinase enzymes. A number of researches have been focusing on how to block EGFR kinase enzyme activity, applying synthetic organic molecules [26] such as imatinib [27], which is used in treating gastrointestinal stromal tumors (GISTs), chronic myelogenous leukemia (CML) and malignancies. Erlotinib [28], is used in the treatment of pancreatic cancer, non-small cell

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Discussion

Conclusion