Current Situation and Future of Aurora Kinase Inhibitors
Posted: Dec 26, 2022
Serine/threonine kinases that are controlled by the cell cycle and are crucial for mitosis make up the Aurora kinase family. They control key mitotic processes such centrosome maturation, chromosomal alignment, chromosome segregation, and cytokinesis by orchestrating their activity and protein production, which is cell cycle-regulated and peaks during mitosis.
The Aurora kinase family in humans is made up of three members: Aurora-A, Aurora-B, and Aurora-C. These three proteins all have a conserved C-terminal catalytic domain, but they have different subcellular localizations, substrate preferences, and mitotic functions. In addition, it has been discovered that Aurora-A and Aurora-B are overexpressed in a range of malignant malignancies.
These findings sparked a variety of initiatives by academic and pharmaceutical institutions that resulted in the identification of small molecule Aurora kinase inhibitors as potential anti-cancer agents.
Inhibitors of Aurora Kinase in Hematologic Malignancies
The most profound explanation for the limited response of Aurora kinase inhibitors in solid tumors in a clinical setting may be the requirement for drug exposures through multiple cell cycles (for the Aurora-B and pan Aurora inhibitors) or for a prolonged time in mitosis (for the Aurora-A inhibitors) to induce their maximum effect in tumor cells prior to the onset of severe toxic effects like neutropenia.
As was previously noted, the clinical assessment of Aurora kinase inhibitors revealed toxicities that are consistent with the mode of action for this class of drugs. The effectiveness of Aurora kinase inhibitors against solid tumors in clinical settings is modest, but overall, they have shown more promise against hematologic malignancies. The reported strong response in hematologic cancer patients may be connected to the disease's secondary pharmacology, which several of these inhibitor’s display, as well as the proliferation rate of the patients' tumors.
Inhibitors of Aurora and DNA damage
A lot of work has gone into examining various strategies to improve the effects of Aurora kinase inhibitors in preclinical models and in clinical trials, including examining Aurora-function A's in the DNA-damage response (DDR). It is well known that Aurora-A activity is crucial for a healthy DDR and is strictly controlled during the reaction to genotoxic substances. The DDR and cell cycle are intricately related on many different levels.
The cell cycle is often stopped after the homologous recombination (HR) machinery is completely engaged by the activation of the DNA damage checkpoints. When G2/M DNA damage occurs, the checkpoint kinases CHK1 and CHK2 or the ATM/ATR kinases-dependent phosphorylation of PLK1 control the CDC25 phosphatases and WEE1 to halt the cell cycle.
Final Thoughts and Future Plans
At first, solid malignancies including ovarian, breast, lung, and colon were the focus of aurora kinase inhibitors. There was only a little amount of effectiveness against solid tumors seen in clinical studies, despite the widespread usage of many pharmacologic classes of Aurora kinase inhibitors. The sluggish cell growth rate found in solid tumors may be the most logical explanation for this finding.
The more rapidly proliferating bone marrow cells had already been seriously harmed by the time an Aurora kinase inhibitor had an impact on malignancies through several cell cycles and mitoses. The tumors were able to advance due to a therapy hiatus taken to allow the patient to heal. Regarding preclinical examination of drugs, it appears that for cell cycle inhibitors, particularly selective mitotic inhibitors, the efficacy results in clinical trials are not predicted by the pre-clinical efficacy models now in use.
Also Note this: According to that theory, the Chemdiv Compound Collection offers a library of potentially selective Aurora A kinase inhibitors. You may search through more than 10,000 compounds in the aurora libraries by clicking here.
Ricky is a graduate of computer science engineering, a writer and marketing consultant. he continues to study on Nano technology and its resulting benefits to achieving almost there.