Generic placeholder image

Current Reviews in Clinical and Experimental Pharmacology


ISSN (Print): 2772-4328
ISSN (Online): 2772-4336

Review Article

The Application of Kinesin Inhibitors in Medical Issues

Author(s): Mojgan Nejabat, Farzin Hadizadeh and Amirhossein Sahebkar*

Volume 19, Issue 4, 2024

Published on: 23 January, 2024

Page: [370 - 378] Pages: 9

DOI: 10.2174/0127724328277623231204064614

Price: $65


Kinesins are a group of motor proteins in charge of several crucial functions in the cell. These proteins often bind to microtubules and perform their functions using the energy produced by ATP hydrolysis. One function of mitotic kinesin, a subclass of kinesin that is expressed during cell division at the mitotic phase, is to create the mitotic spindle. Uncontrolled cell growth is one trait of cancerous cells. Traditional anticancer medications still used in clinics include taxanes (paclitaxel) and vinca alkaloids (vincristine, vinblastine), which interfere with microtubule dynamics. However, because non-dividing cells like post-mitotic neurons contain microtubules, unwanted side effects like peripheral neuropathy are frequently found in patients taking these medications. More than ten members of the mitotic kinesin family play distinct or complementary roles during mitosis. The mitotic kinesin family's KSP, or Eg5, is regarded as its most dramatic target protein. The current work systematically reviews the use of kinesin inhibitors in the medical field. The challenges of KSP and the practical solutions are also examined, and the outcomes of the previous works are reported. The significant gaps and shortcomings of the related works are also highlighted, which can be an onset topic for future works.

Keywords: Kinesin inhibitors, adenosine triphosphate (ATP), mitotic kinesin, kinesin spindle protein (KSP), microtubule dynamics, cancer treatment.

Graphical Abstract
Fischer PM. Chapter 11 -Cell cycle inhibitors in cancer: Current status and future directions. In: Neidle S, Ed. Cancer Drug Design and Discovery. New York: Academic Press 2008; pp. 253-83.
Sathornsumetee S, Rich JN. Molecularly targeted therapy in neuro-oncology. In: Aminoff MJ, Boller F, Swaab DF, Eds Handbook of Clinical Neurology. Elsevier 2012; pp. 255-78.
Chiba K, Ori-McKenney KM, Niwa S, McKenney RJ. Synergistic autoinhibition and activation mechanisms control kinesin-1 motor activity. Cell Rep 2022; 39(9): 110900.
[] [PMID: 35649356]
Weaver BAA, Cleveland DW. Decoding the links between mitosis, cancer, and chemotherapy: The mitotic checkpoint, adaptation, and cell death. Cancer Cell 2005; 8(1): 7-12.
[] [PMID: 16023594]
Nitta R, Kikkawa M, Okada Y, Hirokawa N. KIF1A alternately uses two loops to bind microtubules. Science 2004; 305(5684): 678-83.
[] [PMID: 15286375]
Sakowicz R, Finer JT, Beraud C, et al. Antitumor activity of a kinesin inhibitor. Cancer Res 2004; 64(9): 3276-80.
[] [PMID: 15126370]
Gascoigne KE, Taylor SS. Cancer cells display profound intra- and interline variation following prolonged exposure to antimitotic drugs. Cancer Cell 2008; 14(2): 111-22.
[] [PMID: 18656424]
Shahin R, Aljamal S. Kinesin spindle protein inhibitors in cancer: From high throughput screening to novel therapeutic strategies. Future Sci OA 2022; 8(3): FSO778.
[] [PMID: 35251692]
Pena A, Sweeney A, Cook AD, Locke J, Topf M, Moores CA. Structure of microtubule-trapped human kinesin-5 and its mechanism of inhibition revealed using cryoelectron microscopy. Structure 2020; 28(4): 450-457.e5.
Webb S. Motility and regulation of kinesin-2: Birkbeck. University of London 2022.
Chamariya R, Suvarna V. Role of KSP inhibitors as anti-cancer therapeutics: An update. Anticancer Agents Med Chem 2022; 22(14): 2517-38.
[] [PMID: 35043768]
Kapoor TM, Mayer TU, Coughlin ML, Mitchison TJ. Probing spindle assembly mechanisms with monastrol, a small molecule inhibitor of the mitotic kinesin, Eg5. J Cell Biol 2000; 150(5): 975-88.
[] [PMID: 10973989]
Shi J, Orth JD, Mitchison T. Cell type variation in responses to antimitotic drugs that target microtubules and kinesin-5. Cancer Res 2008; 68(9): 3269-76.
[] [PMID: 18451153]
Marconi GD, Carradori S, Ricci A, Guglielmi P, Cataldi A, Zara S. Kinesin Eg5 targeting inhibitors as a new strategy for gastric adenocarcinoma treatment. Molecules 2019; 24(21): 3948.
[] [PMID: 31683688]
Sarli V, Giannis A. Targeting the kinesin spindle protein: Basic principles and clinical implications. Clin Cancer Res 2008; 14(23): 7583-7.
[] [PMID: 19047082]
Hopkins SC, Vale RD, Kuntz ID. Inhibitors of kinesin activity from structure-based computer screening. Biochemistry 2000; 39(10): 2805-14.
[] [PMID: 10704233]
Zhang Y, Xu W. Progress on kinesin spindle protein inhibitors as anti-cancer agents. Anticancer Agents Med Chem 2008; 8(6): 698-704.
Wang F, Good JAD, Rath O, et al. Triphenylbutanamines: Kinesin spindle protein inhibitors with in vivo antitumor activity. J Med Chem 2012; 55(4): 1511-25.
[] [PMID: 22248262]
Marcus AI, Peters U, Thomas SL, et al. Mitotic kinesin inhibitors induce mitotic arrest and cell death in Taxol-resistant and -sensitive cancer cells. J Biol Chem 2005; 280(12): 11569-77.
[] [PMID: 15653676]
Zhang YY, Dong LX, Bao HL, Liu Y, An FM, Zhang GW. RETRACTED: Inhibition of interleukin-1β plays a protective role in Alzheimer’s disease by promoting microRNA-9-5p and downregulating targeting protein for xenopus kinesin-like protein 2. Int Immunopharmacol 2021; 97: 107578.
[] [PMID: 33892301]
Myers SM, Collins I. Recent findings and future directions for interpolar mitotic kinesin inhibitors in cancer therapy. Future Med Chem 2016; 8(4): 463-89.
[] [PMID: 26976726]
Cook AD, Roberts AJ, Atherton J, Tewari R, Topf M, Moores CA. Cryo-EM structure of a microtubule-bound parasite kinesin motor and implications for its mechanism and inhibition. J Biol Chem 2021; 297(5): 101063.
[] [PMID: 34375637]
Kevenaar JT, Bianchi S, van Spronsen M, et al. Kinesin-binding protein controls microtubule dynamics and cargo trafficking by regulating kinesin motor activity. Curr Biol 2016; 26(7): 849-61.
[] [PMID: 26948876]
Alves MM, Burzynski G, Delalande JM, et al. KBP interacts with SCG10, linking Goldberg–Shprintzen syndrome to microtubule dynamics and neuronal differentiation. Hum Mol Genet 2010; 19(18): 3642-51.
[] [PMID: 20621975]
Suo C, Deng W, Vu TN, Li M, Shi L, Pawitan Y. Accumulation of potential driver genes with genomic alterations predicts survival of high-risk neuroblastoma patients. Biol Direct 2018; 13(1): 14.
[] [PMID: 30012197]
Lyons DA, Naylor SG, Mercurio S, Dominguez C, Talbot WS. KBP is essential for axonal structure, outgrowth and maintenance in zebrafish, providing insight into the cellular basis of Goldberg-Shprintzen syndrome. Development 2008; 135(3): 599-608.
[] [PMID: 18192286]
Atherton J, Hummel JJA, Olieric N, et al. The mechanism of kinesin inhibition by kinesin-binding protein. eLife 2020; 9: e61481.
[] [PMID: 33252036]
Kenchappa RS, Dovas A, Argenziano MG, et al. Activation of STAT3 through combined SRC and EGFR signaling drives resistance to a mitotic kinesin inhibitor in glioblastoma. Cell Rep 2022; 39(12): 110991.
[] [PMID: 35732128]
Ferro LS, Fang Q, Eshun-Wilson L, et al. Structural and functional insight into regulation of kinesin-1 by microtubule-associated protein MAP7. Science 2022; 375(6578): 326-31.
[] [PMID: 35050657]
Fenton AR, Jongens TA, Holzbaur ELF. Mitochondrial adaptor TRAK2 activates and functionally links opposing kinesin and dynein motors. Nat Commun 2021; 12(1): 4578.
[] [PMID: 34321481]
Ogunwa TH, Taii K, Sadakane K, Kawata Y, Maruta S, Miyanishi T. Morelloflavone as a novel inhibitor of mitotic kinesin Eg5. J Biochem 2019; 166(2): 129-37.
[] [PMID: 30785183]
Kirchhoff D, Stelte-Ludwig B, Lerchen HG, et al. IL3RA-targeting antibody–drug conjugate BAY-943 with a kinesin spindle protein inhibitor payload shows efficacy in preclinical models of hematologic malignancies. Cancers 2020; 12(11): 3464.
[] [PMID: 33233768]
Tao W, South VJ, Zhang Y, et al. Induction of apoptosis by an inhibitor of the mitotic kinesin KSP requires both activation of the spindle assembly checkpoint and mitotic slippage. Cancer Cell 2005; 8(1): 49-59.
[] [PMID: 16023598]
Huszar D, Theoclitou ME, Skolnik J, Herbst R. Kinesin motor proteins as targets for cancer therapy. Cancer Metastasis Rev 2009; 28(1-2): 197-208.
[] [PMID: 19156502]
Song H, Zhou S, Wang R, Li S. Kinesin spindle protein (KSP) inhibitors in combination with chemotherapeutic agents for cancer therapy. ChemMedChem 2013; 8(11): 1736-49.
[] [PMID: 23964020]
Kühne W. Studies on the protoplasm and contractility. Leipzig, W.: Engelmann 1864.
Engelhardt WA, Ljubimowa M. Myosine and adenosinetriphosphatase. In: Source Book in Chemistry, 1900–1950. Harvard University Press 1968; pp. 378-81.
Mottier DM. The behavior of the chromosomes in the spore mother-cells of higher plants and the homology of the pollen and embryo-sac mother-cells. Bot Gaz 1903; 35(4): 250-82.
Gibbons IR, Rowe AJ. Dynein: A protein with adenosine triphosphatase activity from cilia. Science 1965; 149(3682): 424-6.
[] [PMID: 17809406]
Vale R, Reese T, Sheetz M. Identification of a novel force-generating protein, kinesin, involved in microtubule-based motility. Cell 1985; 42(1): 39-50.
[] [PMID: 3926325]
McDonald HB, Stewart RJ, Goldstein LSB. The kinesin-like ncd protein of Drosophila is a minus end-directed microtubule motor. Cell 1990; 63(6): 1159-65.
[] [PMID: 2261638]
Paschal BM, Shpetner HS, Vallee RB. MAP 1C is a microtubule-activated ATPase which translocates microtubules in vitro and has dynein-like properties. J Cell Biol 1987; 105(3): 1273-82.
[] [PMID: 2958482]
Zhang P, Knowles BA, Goldstein LSB, Hawley RS. A kinesin-like protein required for distributive chromosome segregation in Drosophila. Cell 1990; 62(6): 1053-62.
[] [PMID: 2144792]
Wordeman L. How kinesin motor proteins drive mitotic spindle function: Lessons from molecular assays. Semin Cell Dev Biol 2010; 21(3): 260-8.
[] [PMID: 20109570]
Miki H, Okada Y, Hirokawa N. Analysis of the kinesin superfamily: Insights into structure and function. Trends Cell Biol 2005; 15(9): 467-76.
[] [PMID: 16084724]
Sommer A. Kinesin spindle protein inhibitors as novel payload class for ADCs. Ann Oncol 2018; 29: iii5-6.
Smith TE, Hong W, Zachariah MM, et al. Single-molecule inhibition of human kinesin by adociasulfate-13 and -14 from the sponge Cladocroce aculeata. Proc Natl Acad Sci 2013; 110(47): 18880-5.
[] [PMID: 24191039]
Xie P. Insight into the chemomechanical coupling mechanism of kinesin molecular motors. Commum Theor Phys 2021; 73(5): 057601.
Konjikusic MJ, Gray RS, Wallingford JB. The developmental biology of kinesins. Dev Biol 2021; 469: 26-36.
[] [PMID: 32961118]
Zhernov I, Diez S, Braun M, Lansky Z. Intrinsically disordered domain of kinesin-3 Kif14 enables unique functional diversity. Curr Biol 2020; 30(17): 3342-51.e5.
Nabb AT, Frank M, Bentley M. Smart motors and cargo steering drive kinesin-mediated selective transport. Mol Cell Neurosci 2020; 103: 103464.
[] [PMID: 31972342]
Liu M, Ran J, Zhou J. Non-canonical functions of the mitotic kinesin Eg5. Thorac Cancer 2018; 9(8): 904-10.
[] [PMID: 29927078]
Li M, Li Y, Jia L, et al. The classification and therapeutic applications of molecular motors. Eur J Med Chem 2021; 3: 100009.
Nejabat M, Hadizadeh F, Nejabat M, Rajabi O. Novel hits for autosomal dominated polycystic kidney disease (ADPKD) targeting derived by in silico screening on ZINC-15 natural product database. J Biomol Struct Dyn 2024; 42(2): 885-902.
[] [PMID: 37029756]
Nejabat M, Ghodsi R, Hadizadeh F. Coumarins and quinolones as effective multiple targeted agents versus COVID-19: An in silico study. Med Chem 2022; 18(2): 220-37.
[] [PMID: 33563156]
Luan Y, Li M, Zhao Y, et al. Centrosomal-associated Proteins: Potential therapeutic targets for solid tumors? Biomed Pharmacother 2021; 144: 112292.
[] [PMID: 34700231]
Takeuchi T, Oishi S, Watanabe T, et al. Structure-activity relationships of carboline and carbazole derivatives as a novel class of ATP-competitive kinesin spindle protein inhibitors. J Med Chem 2011; 54(13): 4839-46.
[] [PMID: 21599002]
Owens B. Kinesin inhibitor marches toward first-in-class pivotal trial. Nat Med 2013; 19(12): 1550.
[] [PMID: 24309639]
Schimmer BP, Parker KL. Adrenocorticotropic hormone; adrenocortical steroids and their synthetic analogs; inhibitors of the synthesis and actions of adrenocortical hormones Goodman & Gilmans the pharmacological basis of therapeutics. (11th ed.). New York: McGraw Hill 2006; pp. 1587-612.
Lucanus AJ, Yip GW. Kinesin superfamily: Roles in breast cancer, patient prognosis and therapeutics. Oncogene 2018; 37(7): 833-8.
[] [PMID: 29059174]
Milic B, Chakraborty A, Han K, Bassik MC, Block SM. KIF15 nanomechanics and kinesin inhibitors, with implications for cancer chemotherapeutics. Proc Natl Acad Sci 2018; 115(20): E4613-22.
[] [PMID: 29703754]
Cho YB, Hong S, Kang KW, Kang JH, Lee SM, Seo YJ. Selective and ATP-competitive kinesin KIF18A inhibitor suppresses the replication of influenza A virus. J Cell Mol Med 2020; 24(10): 5463-75.
[] [PMID: 32253833]
Fan R, Lai KO. Understanding how kinesin motor proteins regulate postsynaptic function in neuron. FEBS J 2022; 289(8): 2128-44.
[] [PMID: 34796656]
Nejabat M, Soltani F, Alibolandi M, et al. Smac peptide and doxorubicin-encapsulated nanoparticles: Design, preparation, computational molecular approach and in vitro studies on cancer cells. J Biomol Struct Dyn 2022; 40(2): 807-19.
[] [PMID: 32912085]
Sebastian J, Rathinasamy K. Benserazide perturbs Kif15-kinesin binding protein interaction with prolonged metaphase and defects in chromosomal congression: A study based on in silico modeling and cell culture. Mol Inform 2020; 39(3): 1900035.
[] [PMID: 31347789]
Mann BJ, Wadsworth P. Kinesin-5 regulation and function in mitosis. Trends Cell Biol 2019; 29(1): 66-79.
[] [PMID: 30220581]
Sawada J, Matsuno K, Ogo N, Asai A. Various effects of two types of kinesin-5 inhibitors on mitosis and cell proliferation. Biochem Pharmacol 2021; 193: 114789.
[] [PMID: 34582773]

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy