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Information and structure of the inhibition of Aurora Kinase B
Along with Aurora Kinase A (AURKA), Aurora Kinase C, and other members of the Aurora Kinase Family, Aurora Kinase B (AURKB) is a mitotic serine/threonine protein kinase (AURKC). AURKB participates in the course of the cell cycle and is a component of the chromosomal passenger protein complex. Numerous malignancies have deregulated AURKB, and its overexpression is commonly associated with tumor cell invasion, metastasis, and treatment resistance.
AURKB has been a popular therapeutic target, which has sparked the creation of small molecule inhibitors. This review covers recent research on the function of AURKB in tumor growth, drug resistance associated with treatment, and its inhibition as a possible cancer therapeutic approach. We go through preclinical and clinically ongoing AURKB inhibitors as well as combination studies combining AURKB inhibition with various treatment modalities.
Three members of the gene family make up the protein serine/threonine kinases known as aurora kinases (AURKs): aurora kinase A (AURKA), aurora kinase B (AURKB), and aurora kinase C. (AURKC).
AURKs are important cell cycle regulators, with AURKA and AURKB being important in mitosis and AURKC being important in gametogenesis. The kinase domain of AURKs, which include three distinct domains, is highly homologous across all of its members. The localisation, spatiotemporal expression, and sequence variations in the N-terminal region of AURKs all serve to clearly characterize their roles.
It has been demonstrated that overexpression of AURKs in cancers causes aneuploidy and genomic instability, which promote the growth, invasion, and metastasis of malignancies. Numerous reviews have been written to emphasize the significance of AURKA in cancer, and AURKA and its functions have been the subject of much research. Further research is required to fully understand the role of AURKC in cancer. The AURKB gene family member, a possible therapeutic target, is the subject of this review.
The AURKB gene on chromosome 17 encodes aurora kinase B, which is also known as AIK2, AIM1, ARK2, AIRK2, IPL1, STK1, STK5, and STK12. AURKB, along with the other AURKs, is essential for the control of the cell cycle. The segregation of chromosomes during cell division depends on the phosphorylation of histone H3 by aurora kinases. It has been demonstrated that AURKA and AURKB both phosphorylate histone H3.
Studies using Chinese hamster embryo cells exogenously overexpressing AURKB have clarified the role of increased AURKB in raising the phosphorylation of histone H3 on Ser10 and aneuploidy. By administering these AURKB overexpressing cells to BALB/c nu/nu mice, it was possible to further illustrate in vivo how important AURKB is in transformation. H-Ras-mediated carcinogenesis is also connected to increased AURKB expression.
AURKB has become a key therapeutic target due to its overexpression in numerous tumor types. AURKB activity in diverse malignancies was particularly inhibited by small molecule inhibitors. We concentrate on AURKB and its role in carcinogenesis in this review. We also go over AURKB inhibitors that are in various stages of clinical development as well as AURKB inhibition as a prospective therapeutic approach. AURKB inhibitors' usage in conjunction with other therapeutic targets is also covered.
The AURKB's composition and purpose
Similar to other aurora kinase gene family members, AURKB is made up of three domains:
• N-terminal domain
• kinase domain
• C–terminal domain
All three members of the aurora family have a highly conserved kinase or catalytic domain, however the N-terminal region exhibits varying degrees of sequence dissimilarity, which offers selectivity for protein-protein interactions. AURKB's kinase domain is made up of two lobes: an N-terminal -stranded lobe and a C-terminal -helical lobe. A hinge region that unites these two lobes allows for active kinase conformation.
The catalytic T-loop, which is located in the C-terminal lobe of the kinase domain, autophosphorylates at Thr232 and activates AURKB. AURKB has three different types of degrons that are considered to mediate its degradation: the KEN motif, the D-box, and the DAD/A box. In the catalytic domain, D-boxes are present. While the C-terminal domain includes a D-box, the non-catalytic N-terminal domain has a KEN motif and a DAD/A box.
Conclusions
AURKB is one of the proteins involved in the control of cell cycle, and deregulation of the cell cycle plays a crucial role in the start, development, invasion, and metastasis of malignancies. AURKB promotes the growth of tumors and chemotherapy-related medication resistance. c-Myc, MDM2, MYCN, and cyclin K are a few of the additional proteins that control the expression of AURKB.
Targeting AURKB is becoming more widely accepted as a viable therapeutic approach for treating a variety of cancers. Although the currently known AURKB inhibitors demonstrated therapeutic effectiveness in vitro and in vivo, they have not yet entered the clinic.
Combination treatment using AURKB inhibition in addition to other small molecule inhibitors active against tumors or conventional chemotherapeutic medicines is urgently required and should be sought in order to build up one's arsenal against cancer.
Last Note: This hypothesis is supported by the library of potentially selective Aurora A kinase inhibitors from the Chemdiv Compound Collection. The aurora libraries contain almost 10,000 compounds.