A New CDK2 Inhibitor with 3-Hydrazonoindolin-2-One Scaffold Endowed with Anti-Breast Cancer Activity: Design, Synthesis, Biological Evaluation, and In Silico Insights

Abstract

Background: Cyclin-dependent kinases (CDKs) regulate mammalian cell cycle progression and RNA transcription. Based on the structural analysis of previously reported CDK2 inhibitors, a new compound with 3-hydrazonoindolin-2-one scaffold (HI 5) was well designed, synthesized, and biologically evaluated as a promising anti-breast cancer hit compound. Methods: The potential anti-cancerous effect of HI 5 was evaluated using cytotoxicity assay, flow cytometric analysis of apoptosis and cell cycle distribution, ELISA immunoassay, in vitro CDK2/cyclin A2 activity, and molecular operating environment (MOE) virtual docking studies. Results: The results revealed that HI 5 exhibits pronounced CDK2 inhibitory activity and cytotoxicity in human breast cancer MCF-7 cell line. The cytotoxicity of HI 5 was found to be intrinsically mediated apoptosis, which in turn, is associated with low Bcl-2 expression and high activation of caspase 3 and p53. Besides, HI 5 blocked the proliferation of the MCF-7 cell line and arrested the cell cycle at the G2/M phase. The docking studies did not confirm which one of geometric isomers (syn and anti) is responsible for binding affinity and intrinsic activity of HI 5. However, the molecular dynamic studies have confirmed that the syn-isomer has more favorable binding interaction and thus is responsible for CDK2 inhibitory activity. Discussion: These findings displayed a substantial basis of synthesizing further derivatives based on the 3-hydrazonoindolin-2-one scaffold for favorable targeting of breast cancer.

Identification of CDK2-Related Immune Forecast Model and ceRNA in Lung Adenocarcinoma, a Pan-Cancer Analysis

“…Cell cycle imbalance is common in different tumors ( Chen T. et al, 2021 ). Cell-dependent kinase (CDK) is involved in many tumors related biological processes, such as cell cycle, immune checkpoint ( Hume et al, 2020 ), RNA transcription ( Al-Sanea et al, 2021 ), cell proliferation ( Liu J. et al, 2021 ). Recently, there have been studies on CDK4 ( Pandey et al, 2021 ) and CDK6 ( Pandey et al, 2021 ), but the mechanism of CDK2 ( El-Sattar et al, 2021 ) in cancer is relatively lacking.…”

The Renaissance of Cyclin Dependent Kinase Inhibitors

“…A recent in vitro study demonstrated a new CDK2 inhibitor with 3-hydrazonoindolin-2-one scaffold, called HI 5 ( Figure 10 ). This inhibitor induced intrinsic apoptosis in human breast cancer cell line MCF-2 [ 117 ].…”

Antiproliferative Activity, Multikinase Inhibition, Apoptosis- Inducing Effects and Molecular Docking of Novel Isatin–Purine Hybrids

“…Isatin derivatives have the potential to modulate multiple biological targets, such as histone deacetylase, β-carbonic anhydrase, tyrosine kinase, phosphodiesterase 4B, and tubulin, changing the expression of particular apoptosis-related genes and eventually causing apoptosis [ 19 ]. Furthermore, several potent antitumor agents, such as semaxanib and sunitinib, contain an isatin scaffold ( Figure 1 ), demonstrating that isatin is an effective moiety for the development of novel anticancer agents [ 20 ]. On the other hand, purine-containing compounds such as I and II ( Figure 1 ) were also found to be good anticancer agents due to their multitarget effects, including the inhibition of the activity of CDKs, EGFR, VEGFR2, HDAC, mTOR, MAPK and MNK [ 21 , 22 , 23 , 24 , 25 , 26 , 27 ].…”