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Current Biotechnology

Editor-in-Chief

ISSN (Print): 2211-5501
ISSN (Online): 2211-551X

Research Article

Prospection of Therapeutic Agents Targeting Aurora Kinase, a Protein in the Treatment of Acute Lymphoblastic Leukemia

Author(s): Ana Beatriz da Lima, Felipe Pantoja Mesquita, Pedro Filho Noronha Souza, Raquel Carvalho Montenegro and Claudia Roberta de Andrade*

Volume 13, Issue 1, 2024

Published on: 03 August, 2023

Page: [37 - 45] Pages: 9

DOI: 10.2174/2211550112666230731104518

Price: $65

Abstract

Background: Acute lymphoblastic leukemia (ALL) is characterized by an imbalance in the production and development of hematopoietic lymphoid cells, a malignant disease capable of affecting the proliferation-selection of hematopoietic cells. The Aurora kinase A protein participates in several steps of the mitosis process. Its deregulation can trigger the process of carcinogenesis, which has become a therapeutic target of interest for computational prediction and the development of inhibitory drugs. Studies report its overexpression in malignant cells of patients with ALL.

Objective: The present study aims to prospect new molecules to identify a potential inhibitor of Aurora kinase A for the pharmaceutical market.

Methodology: Virtual screening and molecular docking study was performed using the MCULE and DockThor web servers. The pharmacodynamic and pharmacokinetic profile of the molecules were evaluated using the Swiss ADME and ProTox-II programs were used.

Results: Ten molecules were identified by virtual screening, in which only two, MCULE-349 and MCULE-796, showed the best score, binding, at the site of action of the protein, interacting positively with amino acids, lipid-soluble molecules with low toxicity and with violation of only 1 Lipinski rule.

Conclusion: Both molecules interact with the site of action, acting as inhibitors or blockers of the catalytic site, becoming potential Aurora kinase A inhibitors and anticancer molecules.

Keywords: Leukemia, acute lymphoblastic leukemia, aurora kinase A, molecular docking, virtual screening, targeted therapy.

Graphical Abstract
[1]
Burke VP, Startzell JM. The Leukemias. Oral Maxillofac Surg Clin North Am 2008; 20(4): 597-608.
[http://dx.doi.org/10.1016/j.coms.2008.06.011] [PMID: 18940626]
[2]
Parkin DM, Stiller CA, Draper GJ, Bieber CA. The international incidence of childhood cancer. Int J Cancer 1988; 42(4): 511-20.
[http://dx.doi.org/10.1002/ijc.2910420408] [PMID: 3170025]
[3]
Shin SY, Lee H, Lee ST, et al. Recurrent somatic mutations and low germline predisposition mutations in Korean ALL patients. Sci Rep 2021; 11(1): 8893.
[http://dx.doi.org/10.1038/s41598-021-88449-4] [PMID: 33903686]
[4]
Hauptmann M, Daniels RD, Cardis E, et al. Epidemiological studies of low-dose ionizing radiation and cancer: Summary bias assessment and meta-analysis. J Natl Cancer Inst Monogr 2020; 2020(56): 188-200.
[http://dx.doi.org/10.1093/jncimonographs/lgaa010] [PMID: 32657347]
[5]
Pui CH, Robison LL, Look AT. Acute lymphoblastic leukaemia. Lancet 2008; 371(9617): 1030-43.
[http://dx.doi.org/10.1016/S0140-6736(08)60457-2] [PMID: 18358930]
[6]
Instituto Nacional de Câncer. Estatísticas de câncer 2021. Available From: https://www.inca.gov.br/numeros-de-cancer
[7]
Kumar Malani A, Gupta C, Rangineni R, Singh J, Ammar H. Concomitant presentation of acute myeloid leukemia with T-cell large granular lymphocytic leukemia. Acta Oncol 2007; 46(2): 247-9.
[http://dx.doi.org/10.1080/02841860600827139] [PMID: 17453377]
[8]
Instituto Nacional de Câncer. Tipos de câncer 2021. Available From: [https://www.gov.br/inca/pt-br/assuntos/cancer/tipos/leucemia]
[9]
Brunning RD. Classification of acute leukemias. Semin Diagn Pathol 2003; 20(3): 142-53.
[http://dx.doi.org/10.1016/S0740-2570(03)00031-5] [PMID: 14552428]
[10]
Vardiman JW, Thiele J, Arber DA, et al. The 2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia: Rationale and important changes. Blood 2009; 114(5): 937-51.
[http://dx.doi.org/10.1182/blood-2009-03-209262] [PMID: 19357394]
[11]
Bennet JM, Catovsky D, Marie-Theregse D, et al. Proposals for the Classification of the Acute Leukaemias French-American-British (FAB) Co-operative Group B J Haem 1976; 33: 451-8.
[http://dx.doi.org/10.1111/j.1365-2141.1976.tb03563.x]
[12]
Byrd JC, Hillmen P, Ghia P, et al. Acalabrutinib versus ibrutinib in previously treated chronic lymphocytic leukemia: Results of the first randomized phase III trial. J Clin Oncol 2021; 39(31): 3441-52.
[http://dx.doi.org/10.1200/JCO.21.01210] [PMID: 34310172]
[13]
Hosseini MS, Jafari L, Yami A, Gharehbaghian A. Therapeutic approaches for relapsed/refractory adult acute lymphoblastic leukemia (ALL), a review on monoclonal antibodies and targeted therapies. Indian J Cancer 2022; 59(1): 4-11.
[PMID: 35645049]
[14]
Liu Y, Wang S, Schubert ML, et al. CD33 ‐directed immunotherapy with third‐generation chimeric antigen receptor T cells and gemtuzumab ozogamicin in intact and CD33 ‐edited acute myeloid leukemia and hematopoietic stem and progenitor cells. Int J Cancer 2022; 150(7): 1141-55.
[http://dx.doi.org/10.1002/ijc.33865] [PMID: 34766343]
[15]
Wong YH, Chiu CC, Lin CL, et al. A new era for cancer target therapies: Applying systems biology and computer-aided drug design to cancer therapies. Curr Pharm Biotechnol 2016; 17(14): 1246-67.
[http://dx.doi.org/10.2174/1389201017666161019160606] [PMID: 27774890]
[16]
Yan M, Wang C, He B, et al. Aurora-A Kinase: A potent oncogene and target for cancer therapy. Med Res Rev 2016; 36(6): 1036-79.
[http://dx.doi.org/10.1002/med.21399] [PMID: 27406026]
[17]
Fu J, Bian M, Jiang Q, Zhang C. Roles of Aurora kinases in mitosis and tumorigenesis. Mol Cancer Res 2007; 5(1): 1-10.
[http://dx.doi.org/10.1158/1541-7786.MCR-06-0208] [PMID: 17259342]
[18]
Carpinelli P, Moll J. Aurora kinases and their inhibitors: More than one target and one drug. Adv Exp Med Biol 2008; 610: 54-73.
[http://dx.doi.org/10.1007/978-0-387-73898-7_5] [PMID: 18593015]
[19]
Fatma H, Siddique HR. AURORA KINASE A and related downstream molecules: A potential network for cancer therapy. Adv Protein Chem Struct Biol 2023; 134: 115-45.
[http://dx.doi.org/10.1016/bs.apcsb.2022.10.005] [PMID: 36858732]
[20]
Rybin MJ, Laverde-Paz MJ, Suter RK, et al. A dual aurora and lim kinase inhibitor reduces glioblastoma proliferation and invasion. Bioorg Med Chem Lett 2022; 61: 128614.
[http://dx.doi.org/10.1016/j.bmcl.2022.128614] [PMID: 35151865]
[21]
Peng F, Xu J, Cui B, et al. Oncogenic AURKA-enhanced N6-methyladenosine modification increases DROSHA mRNA stability to transactivate STC1 in breast cancer stem-like cells. Cell Res 2021; 31(3): 345-61.
[http://dx.doi.org/10.1038/s41422-020-00397-2] [PMID: 32859993]
[22]
Li G, Tian Y, Gao Z. The role of AURKA/miR ‐199b‐3p in hepatocellular carcinoma cells. J Clin Lab Anal 2022; 36(12): e24758.
[http://dx.doi.org/10.1002/jcla.24758] [PMID: 36377304]
[23]
Wang F, Zhang H, Wang H, Qiu T, He B, Yang Q. Combination of AURKA inhibitor and HSP90 inhibitor to treat breast cancer with AURKA overexpression and TP53 mutations. Med Oncol 2022; 39(12): 180.
[http://dx.doi.org/10.1007/s12032-022-01777-x] [PMID: 36071247]
[24]
Jung P, Horst D, Kirchner T, Klauschen F, Neumann J. AURKA is a prognostic biomarker for good overall survival in stage II colorectal cancer patients. Pathol Res Pract 2022; 235: 153936.
[http://dx.doi.org/10.1016/j.prp.2022.153936] [PMID: 35576834]
[25]
Xie Y, Zhu S, Zhong M, et al. Inhibition of Aurora Kinase A Induces Necroptosis in Pancreatic Carcinoma. Gastroenterology 2017; 153(5): 1429-1443.e5.
[http://dx.doi.org/10.1053/j.gastro.2017.07.036] [PMID: 28764929]
[26]
Moreira-Nunes CA, Mesquita FP, Portilho AJS, et al. Targeting aurora kinases as a potential prognostic and therapeutical biomarkers in pediatric acute lymphoblastic leukaemia. Sci Rep 2020; 10(1): 21272.
[http://dx.doi.org/10.1038/s41598-020-78024-8] [PMID: 33277547]
[27]
Guedes IA, Costa LSC, dos Santos KB, et al. Drug design and repurposing with DockThor-VS web server focusing on SARS-CoV-2 therapeutic targets and their non-synonym variants. Sci Rep 2021; 11(1): 5543.
[http://dx.doi.org/10.1038/s41598-021-84700-0] [PMID: 33692377]
[28]
Amaral JL, Oliveira JTA, Lopes FES, et al. Quantum biochemistry, molecular docking, and dynamics simulation revealed synthetic peptides induced conformational changes affecting the topology of the catalytic site of SARS-CoV-2 main protease. J Biomol Struct Dyn 2021; 39: 1-13.
[PMID: 33949286]
[29]
Daina A, Michielin O, Zoete V. SwissADME: A free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Sci Rep 2017; 7(1): 42717.
[http://dx.doi.org/10.1038/srep42717] [PMID: 28256516]
[30]
Banerjee P, Eckert AO, Schrey AK, Preissner R. ProTox-II: A webserver for the prediction of toxicity of chemicals. Nucleic Acids Res 2018; 46(W1): W257-63.
[http://dx.doi.org/10.1093/nar/gky318] [PMID: 29718510]
[31]
Schöffski P, Jones SF, Dumez H, et al. Phase I, open-label, multicentre, dose-escalation, pharmacokinetic and pharmacodynamic trial of the oral aurora kinase inhibitor PF-03814735 in advanced solid tumours. Eur J Cancer 2011; 47(15): 2256-64.
[http://dx.doi.org/10.1016/j.ejca.2011.07.008] [PMID: 21852114]
[32]
Min YH, Kim W, Kim JE. The Aurora kinase A inhibitor TC-A2317 disrupts mitotic progression and inhibits cancer cell proliferation. Oncotarget 2016; 7(51): 84718-35.
[http://dx.doi.org/10.18632/oncotarget.12448] [PMID: 27713168]
[33]
Kohlrausch FB, Carracedo Á, Hutz MH. Characterization of CYP1A2, CYP2C19, CYP3A4 and CYP3A5 polymorphisms in South Brazilians. Mol Biol Rep 2014; 41(3): 1453-60.
[http://dx.doi.org/10.1007/s11033-013-2990-8] [PMID: 24443221]
[34]
Khan MKA, Ahmad S, Rabbani G, Shahab U, Khan MS. Target‐based virtual screening, computational multiscoring docking and molecular dynamics simulation of small molecules as promising drug candidate affecting kinesin‐like protein KIFC1. Cell Biochem Funct 2022; 40(5): 451-72.
[http://dx.doi.org/10.1002/cbf.3707] [PMID: 35758564]
[35]
Ibrahim ZYU, Uzairu A, Shallangwa G, Abechi S. Molecular docking studies, drug-likeness and in-silico ADMET prediction of some novel β-Amino alcohol grafted 1,4,5-trisubstituted 1,2,3-triazoles derivatives as elevators of p53 protein levels. Sci Am 2020; 10: 1-8.
[36]
Lipinski CA. Drug-like properties and the causes of poor solubility and poor permeability. J Pharmacol Toxicol Methods 2000; 44(1): 235-49.
[http://dx.doi.org/10.1016/S1056-8719(00)00107-6] [PMID: 11274893]
[37]
Russo DP, Strickland J, Karmaus AL, et al. Nonanimal Models for Acute Toxicity Evaluations: Applying Data-Driven Profiling and Read-Across. Environ Health Perspect 2019; 127(4): 047001.
[http://dx.doi.org/10.1289/EHP3614] [PMID: 30933541]

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