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Aurora Kinase B Inhibition: a Potential Therapeutic Strategy for Cancer

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Aurora Kinase B Inhibition: a Potential Therapeutic Strategy for Cancer molecules Review Aurora Kinase B Inhibition: A Potential Therapeutic Strategy for Cancer Naheed Arfin Borah 1,2 and Mamatha M. Reddy 1,2,* 1 The Operation Eyesight Universal Institute for Eye Cancer, L.V. Prasad Eye Institute, Bhubaneswar 751024, India; [email protected] 2 School of Biotechnology, KIIT University, Bhubaneswar 751024, India * Correspondence: [email protected] or [email protected]; Tel.: +91-6743987175 Abstract: Aurora kinase B (AURKB) is a mitotic serine/threonine protein kinase that belongs to the aurora kinase family along with aurora kinase A (AURKA) and aurora kinase C (AURKC). AURKB is a member of the chromosomal passenger protein complex and plays a role in cell cycle progression. Deregulation of AURKB is observed in several tumors and its overexpression is frequently linked to tumor cell invasion, metastasis and drug resistance. AURKB has emerged as an attractive drug target leading to the development of small molecule inhibitors. This review summarizes recent findings pertaining to the role of AURKB in tumor development, therapy related drug resistance, and its inhibition as a potential therapeutic strategy for cancer. We discuss AURKB inhibitors that are in preclinical and clinical development and combination studies of AURKB inhibition with other therapeutic strategies. Keywords: aurora kinase B (AURKB); cancer; AURKB regulation; AURKB inhibitors; therapy related drug resistance; combination therapy Citation: Borah, N.A.; Reddy, M.M. Aurora Kinase B Inhibition: A Potential Therapeutic Strategy for 1. Introduction Cancer. Molecules 2021, 26, 1981. Aurora kinases (AURKs) are protein serine/threonine kinases consisting of three https://doi.org/10.3390/ members in the gene family—aurora kinase A (AURKA), aurora kinase B (AURKB) and molecules26071981 aurora kinase C (AURKC) [1]. AURKs are critical regulators of the cell cycle, with AURKA and AURKB playing a key function in mitosis [1], whereas AURKC has a significant role in Academic Editor: Roberta Bortolozzi gametogenesis [2,3]. AURKs have three different domains, of which the kinase domain shares a high degree of homology among all the members [4]. The functions of AURKs are Received: 4 March 2021 well-defined by their localization and spatio-temporal expression [5] and also the sequence Accepted: 23 March 2021 Published: 1 April 2021 differences in their N-terminal region [4]. Overexpression of AURKs in tumors has been shown to trigger aneuploidy and genomic instability [6] that leads to tumor development, Publisher’s Note: MDPI stays neutral invasion and metastasis. AURKA and its functions have been widely investigated and with regard to jurisdictional claims in several reviews were authored to highlight its importance in cancer [7,8]. The role of published maps and institutional affil- AURKC in cancer is not completely understood and needs further investigations. This iations. review focuses on AURKB, a potential drug target from the AURK gene family. Aurora kinase B is encoded by the AURKB gene located on chromosome 17 and is also known by other names including AIK2, AIM1, ARK2, AIRK2, IPL1, STK1, STK5 and STK12. AURKB along with other AURKs plays a vital role in the regulation of cell cycle. Phosphorylation of histone H3 by aurora kinases is essential for chromosome segregation Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. during cell division. Both AURKA and AURKB have been shown to phosphorylate histone This article is an open access article H3 [9]. The role of elevated AURKB in increasing the phosphorylation of histone H3 on distributed under the terms and Ser10 and aneuploidy has been elucidated in studies involving Chinese hamster embryo conditions of the Creative Commons cells exogenously overexpressing AURKB. The function of AURKB in transformation was Attribution (CC BY) license (https:// further demonstrated in vivo by injecting these AURKB overexpressing cells into BALB/c creativecommons.org/licenses/by/ nu/nu mice [10]. Induced AURKB expression is also linked to tumorigenesis mediated 4.0/). by H-Ras [11]. Molecules 2021, 26, 1981. https://doi.org/10.3390/molecules26071981 https://www.mdpi.com/journal/molecules Molecules 2021, 26, x FOR PEER REVIEW 2 of 29 Molecules 2021, 26, 1981 into BALB/c nu/nu mice [10]. Induced AURKB expression is also linked to tumorigenesis2 of 30 mediated by H-Ras [11]. Based on its overexpression in various tumors, AURKB has emerged as an important drug Basedtarget. onSmall its overexpressionmolecule inhibitors in various were designed tumors, to AURKB specifically has emerged inhibit AURKB as an impor- func- tiontant in drug various target. tumors. Small In molecule this review, inhibitors we focus were on designed AURKB to and specifically its function inhibit and AURKBderegu- lationfunction in tumorigenesis. in various tumors. Further, In we this discuss review, AURKB we focus inhibition on AURKB as a promising and its function therapeutic and strategyderegulation and AURKB in tumorigenesis. inhibitors Further,that are wein di discussfferent AURKB phases inhibitionof clinical asdevelopment. a promising ther-Ad- ditionally,apeutic strategy the use and of AURKBAURKB inhibitorsinhibitors that in co arembination in different with phases other of therapeutic clinical development. targets is discussed.Additionally, the use of AURKB inhibitors in combination with other therapeutic targets is discussed. 2. Structure and Function of AURKB 2. StructureAURKB, and similar Function to other of AURKBmembers of the aurora kinase gene family, is composed of three AURKB,domains: similar (i) N-terminal to other membersdomain, (ii) of thekinase aurora domain, kinase and gene (iii) family, C–terminal is composed domain of [12].three The domains: kinase (i) domain N-terminal or catalytic domain, domain (ii) kinase is domain,highly conserved and (iii) C–terminal between all domain the three [12]. membersThe kinase of domain the aurora or catalytic family, whereas domain isthe highly N-terminal conserved domain between shows all a the varied three degree members of sequenceof the aurora dissimilarity family, whereas that provides the N-terminal selectivity domain for protein-protein shows a varied interactions. degree of sequence The ki- nasedissimilarity domain in that AURKB provides is composed selectivity of for a protein-proteinβ-stranded lobe interactions. on the N-terminal The kinase side domainand an αin-helical AURKB lobe is on composed the C-terminal of a β -strandedside. These lobe two on lobes the are N-terminal connected side together and an byα a-helical hinge region,lobe on which the C-terminal permits active side. kinase These conformati two lobes areon [13]. connected The C-terminal together bylobe a hingeof the region,kinase domainwhich permits contains active the kinasecatalytic conformation T-loop whose [13 ].auto-phosphorylation The C-terminal lobe ofat theThr232 kinase results domain in AURKBcontains activation. the catalytic AURKB T-loop contains whose auto-phosphorylation three types of degrons; at Thr232 KEN motif, results D-box in AURKB and DAD/Aactivation. box that AURKB are thought contains to threemediate types its degradation. of degrons; KENThe catalytic motif, D-boxdomain and contains DAD/A D- boxesbox that (reviewed are thought in [14]). to mediate The non-catalytic its degradation. N-terminal The catalytic domain domain has a KEN contains motif D-boxes and a DAD/A(reviewed box, in whereas [14]). The the non-catalytic C-terminal N-terminaldomain has domain a D-box. has However, a KEN motif Nguyen and aet DAD/A al., has box, whereas the C-terminal domain has a D-box. However, Nguyen et al., has showed showed that only N-terminal KEN and DAD/A boxes are responsible for AURKB degra- that only N-terminal KEN and DAD/A boxes are responsible for AURKB degradation [15] dation [15] (Figure 1a). (Figure1a). Figure 1. (a) Domain structure of AURKB showing catalytic and non-catalytic domains [14,16]. Figure 1. (a) Domain structure of AURKB showing catalytic and non-catalytic domains [14,16]. (b) (b) Functions of AURKB in normal cells and cancer cells [8,14]. Functions of AURKB in normal cells and cancer cells [8,14]. The binding of E2F1, E2F4, FoxM1 and DP-2 to the AURKB promoter transcrip- tionally regulates AURKB. These transcription factors bind to the cell cycle-dependent element (CDE) and cell cycle gene homology region (CHR) located up-stream of the tran- scription start-site (Figure1b; reviewed in [ 14]). AURKB is an essential member of the chromosomal passenger complex (CPC) which additionally includes INCENP, survivin Molecules 2021, 26, 1981 3 of 30 and borealin [17,18]. AURKB is located on the chromatin before the onset of mitosis and promotes chromosome condensation by the phosphorylation of histone H3 and centrosome protein A (CENP-A) [19]. In pro-metaphase, AURKB, as part of the CPC, moves towards the kinetochores and is associated with repairing faulty spindle kinetochore attachments (spindle assembly checkpoint) [20]. AURKB ensures adequate alignment and segregation of sister chromatids and relocates to the microtubules during the transition from metaphase to anaphase [21]. AURKB regulates the distribution of Kif-2A and limits Kif-2A-controlled depolymerization of microtubules, thereby, mediating microtubule formation and func- tioning [22]. AURKB has also been implicated in cytokinesis, explained by its presence at the mid-body during telophase [23–25]. 3. Deregulation of AURKB in Cancer Drawing parallels with the functions of AURKB in mitosis, it is anticipated
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