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Review

Kinesin Spindle Protein Inhibitors in Cancer: From High Throughput Screening to Novel Therapeutic Strategies

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Article: FSO778 | Received 23 Sep 2021, Accepted 14 Dec 2021, Published online: 21 Feb 2022

References

  • SongH , ZhouS , WangRet al.Kinesin spindle protein (KSP) inhibitors in combination with chemotherapeutic agents for cancer therapy. ChemMedChem8, 1736–1749 (2013).
  • KonjikusicMJ , GrayRS , WallingfordJB. The developmental biology of kinesins. Dev. Biol.469, 26–36 (2021).
  • HanssonK , RadkeK , AaltonenKet al.Therapeutic targeting of KSP in preclinical models of high-risk neuroblastoma. Sci. Transl. Med.12, 1–17 (2020).
  • Garcia-SaezI , SkoufiasDA. Eg5 targeting agents: from new anti-mitotic based inhibitor discovery to cancer therapy and resistance. Biochem. Pharmacol.184, 114364 (2021).
  • MarshallCG , TorrentM , WilliamsOet al.Characterization of inhibitor binding to human kinesin spindle protein by site-directed mutagenesis. Arch. Biochem. Biophys.484, 1–7 (2009).
  • ShahinR , ShaheenO , El-DahiyatF , HabashM , SaffourS. Research advances in kinase enzymes and inhibitors for cardiovascular disease treatment. 3(4), FSO204 (2017).
  • El-NassanHB. Advances in the discovery of kinesin spindle protein (Eg5) inhibitors as antitumor agents. Eur. J. Med. Chem.62, 614–631 (2013).
  • ShahinR , Al-HashimiNN , DaoudNE , AljamalS , ShaheenO. QSAR-guided pharmacophoric modeling reveals important structural requirements for Polo kinase 1 (Plk1) inhibitors. J. Mol. Graph. Model.109, 108022 (2021).
  • TischerJ , GergelyF. Anti-mitotic therapies in cancer. J. Cell Biol.218, 10–11 (2019).
  • SwellmeenL , ShahinR , Al-HiariYet al.Structure based drug design of Pim-1 kinase followed by pharmacophore guided synthesis of Quinolone-based inhibitors. Bioorg. Med. Chem. 25(17), 4855–4875 (2017).
  • ShahinR , SwellmeenL , ShaheenO , AboalhaijaN , HabashM. Identification of novel inhibitors for Pim-1 kinase using pharmacophore modeling based on a novel method for selecting pharmacophore generation subsets. J. Comput. Aided Mol. Des.30(1), 39–68 (2016).
  • NovaisP , SilvaPMA , AmorimI , BousbaaH. Second-generation antimitotics in cancer clinical trials. Pharmaceutics13(7), 1011 (2021).
  • MayerTU , KapoorTM , HaggartySJ , KingRW , SchreiberSL , MitchisonTJ. Smart molecule inhibitor of mitotic spindle bipolarity identified in a phenotype-based screen. Science286, 971–974 (1999).
  • MyersS , CollinsI. Recent findings and future directions for interpolar mitotic kinesin inhibitors in cancer therapy. Future Med. Chem.8, 463–489 (2016).
  • JiangC , ZhangX , ShenZ , QidongY. Kinesin spindle protein inhibitors. Prog. Chem.22, 153–162 (2010).
  • GartnerM , Sunder-PlassmannN , SeilerJet al.Development and biological evaluation of potent and specific inhibitors of mitotic kinesin Eg5. Chembiochem6, 1173–1177 (2005).
  • KaanHYK , UlaganathanV , RathOet al.Structural basis for inhibition of Eg5 by dihydropyrimidines: stereoselectivity of antimitotic inhibitors enastron, dimethylenastron and fluorastrol. J. Med. Chem.53, 5676–5683 (2010).
  • HamelE , HamelE. Identification of novel antimitotic agents acting at the tubulin level by computer-assisted evaluation of differential cytotoxicity data. Cancer Res.52, 3892–3900 (1992).
  • BrierS , LemaireD , DeBonisS , ForestE , KozielskiF. Identification of the protein binding region of S-trityl-L-cysteine, a new potent inhibitor of the mitotic kinesin Eg5. Biochemistry43, 13072–13082 (2004).
  • FukaiR , OgoN , IchidaTet al.Design, synthesis, and evaluation of a novel prodrug, a S-trityl-L-cysteine derivative targeting kinesin spindle protein. Eur. J. Med. Chem.215, 113288 (2021).
  • PurcellJW , DavisJ , ReddyMet al.Activity of the kinesin spindle protein inhibitor ispinesib (SB-715992) in models of breast cancer. Clin. Cancer Res.16, 566–576 (2010).
  • HuszarD , TheoclitouME , SkolnikJ , HerbstR. Kinesin motor proteins as targets for cancer therapy. Cancer Metastasis Rev.28, 197–208 (2009).
  • JacksonJR , PatrickDR , DarMM , HuangPS. Targeted anti-mitotic therapies: can we improve on tubulin agents?Nat. Rev. Cancer.7, 107–117 (2007).
  • ŠkubníkJ , JurášekM , RumlT , RimpelováS. Mitotic poisons in research and medicine. Molecules25(20), 4632 (2020).
  • KnoxJJ , GillS , SynoldTWet al.A phase II and pharmacokinetic study of SB-715992, in patients with metastatic hepatocellular carcinoma: a study of the National Cancer Institute of Canada Clinical Trials Group (NCIC CTG IND.168). Invest. New Drugs26, 265–272 (2008).
  • TangPA , SiuLL , ChenEXet al.Phase II study of ispinesib in recurrent or metastatic squamous cell carcinoma of the head and neck. Invest. New Drugs26, 257–264 (2008).
  • StevensM , FrobisherC , HawkinsMet al.The British Childhood Cancer Survivor Study: objectives, methods, population structure, response rates and initial descriptive information. Pediatr. Blood Cancer50, 1018–1025 (2008).
  • ChenLC , RosenLS , IyengarTet al.First-in-human study with ARQ 621, a novel inhibitor of Eg5: final results from the solid tumors cohort. J. Clin. Oncol.29, 3076 (2011).
  • U.S. National Libaray of Medicine. clinicaltrials.gov. http://www.clinicaltrials.gov
  • NakaiR , IidaSI , TakahashiTet al.K858, a novel inhibitor of mitotic kinesin Eg5 and antitumor agent, induces cell death in cancer cells. Cancer Res.69, 3901–3909 (2009).
  • SzeligaM. Thiadiazole derivatives as anticancer agents. Pharmacol. Reports72, 1079–1100 (2020).
  • TaglieriL , RubinacciG , GiuffridaAet al.The kinesin Eg5 inhibitor K858 induces apoptosis and reverses the malignant invasive phenotype in human glioblastoma cells. Invest. New Drugs36, 28–35 (2018).
  • DeIuliis F , TaglieriL , SalernoGet al.The kinesin Eg5 inhibitor K858 induces apoptosis but also survivin-related chemoresistance in breast cancer cells. Invest. New Drugs34, 399–406 (2016).
  • InfanteJR , PatnaikA , VerschraegenCFet al.Two phase I dose-escalation studies exploring multiple regimens of litronesib (LY2523355), an Eg5 inhibitor, in patients with advanced cancer. Cancer Chemother. Pharmacol.79, 315–326 (2017).
  • WakuiH , YamamotoN , KitazonoSet al.A phase I and dose-finding study of LY2523355 (litronesib), an Eg5 inhibitor, in Japanese patients with advanced solid tumors. Cancer Chemother. Pharmacol.74, 15–23 (2014).
  • CoxCD , ColemanPJ , BreslinMJet al.Kinesin Spindle Protein (KSP) inhibitors. 9. Discovery of (2S)-4-(2,5-difluorophenyl)-N-[(3R,4S)-3-fluoro-1-methylpiperidin-4-yl]-2-(hydroxymethyl)-N-methyl-2-phenyl-2,5-dihydro-1H-pyrrole-1-carboxamide (MK-0731) for the treatment of taxane-refractory cancer. J. Med. Chem.51, 4239–4252 (2008).
  • TheoclitouM , AquilaB , BlockMHet al.Cancer & Infection Research Area, AstraZeneca, Alderley Park, Macclesfield, Cheshire, SK10 4TG, United Kingdom Cancer & Infection Research Area, AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States. 6734–6750 (2011).
  • HollebecqueA , DeutschE , MassardCet al.A phase I, dose-escalation study of the Eg5-inhibitor EMD 534085 in patients with advanced solid tumors or lymphoma. Invest. New Drugs31, 1530–1538 (2013).
  • KochG. Medicinal Chemistry. Chimia (Aarau).71, 643 (2017).
  • PeñaA , SweeneyA , CookAD , LockeJ , TopfM , MooresCA. Structure of microtubule-trapped human kinesin-5 and its mechanism of inhibition revealed using cryoelectron microscopy. Structure28, 450–457.e5 (2020).
  • ShahinR , MansiI , SwellmeenLet al.Ligand-based computer aided drug design reveals new tropomycin receptor kinase a (TrkA) inhibitors. J. Mol. Graph. Model.80, 327–352 (2018).
  • YokoyamaH , SawadaJI , KatohSet al.Structural basis of new allosteric inhibition in kinesin spindle protein eg5. ACS Chem. Biol.10, 1128–1136 (2015).
  • GascoigneKE , TaylorSS. Cancer cells display profound intra- and interline variation following prolonged exposure to antimitotic drugs. Cancer Cell14, 111–122 (2008).
  • Komlodi-PasztorE , SackettDL , FojoAT. Inhibitors targeting mitosis: tales of how great drugs against a promising target were brought down by a flawed rationale. Clin. Cancer Res.18, 51–63 (2012).
  • SarliV , GiannisA. Targeting the kinesin spindle protein: basic principles and clinical implications. Clin. Cancer Res.14, 7583–7587 (2008).
  • Hernández-GarcíaS , San-SegundoL , González-MéndezLet al.The kinesin spindle protein inhibitor filanesib enhances the activity of pomalidomide and dexamethasone in multiple myeloma. Haematologica102, 2113–2124 (2017).
  • AlgarínEM , Hernández-GarcíaS , GarayoaMet al.Filanesib for the treatment of multiple myeloma. Expert Opin. Investig. Drugs29, 5–14 (2020).
  • TunquistB , BrownK , HingoraniGet al.Identification of alpha 1-acid glycoprotein (AAG) as a potential patient selection biomarker for improved clinical activity of the novel KSP inhibitor ARRY-520 in relapsed and refractory multiple myeloma (MM). Blood120, 1868 (2012).
  • TaberneroJ , ShapiroGI , LoRussoPMet al.First-in-humans trial of an RNA interference therapeutic targeting VEGF and KSP in cancer patients with liver involvement. Cancer Discov.3, 406–417 (2013).
  • MrossKB , ScharrD , RichlyHet al.First-in-human study of 4SC-205 (AEGIS), a novel oral inhibitor of Eg5 kinesin spindle protein. J. Clin. Oncol.32, 2564 (2014).
  • ValensinS , GhironC , LamannaCet al.KIF11 inhibition for glioblastoma treatment: reason to hope or a struggle with the brain?BMC Cancer9, 1–14 (2009).
  • VenutoS , MonteonofrioL , CozzolinoFet al.TRIM8 interacts with KIF11 and KIFC1 and controls bipolar spindle formation and chromosomal stability. Cancer Lett.473, 98–106 (2020).
  • WangF , LinSL. Knockdown of kinesin KIF11 abrogates directed migration in response to epidermal growth factor-mediated chemotaxis. Biochem. Biophys. Res. Commun.452, 642–648 (2014).
  • LiB , ZhuFC , YuSXet al.Suppression of KIF22 inhibits cell proliferation and xenograft tumor growth in colon cancer. Cancer Biother. Radiopharm.35, 50–57 (2020).
  • ZuckermanJE , DavisME. Clinical experiences with systemically administered siRNA-based therapeutics in cancer. Nat. Rev. Drug Discov.14, 843–856 (2015).
  • KarpovAS , Nieto-OberhuberCM , AbramsTet al.Discovery of potent and selective antibody–drug conjugates with Eg5 inhibitors through linker and payload optimization. ACS Med. Chem. Lett.10, 1674–1679 (2019).
  • ŁomzikM , HanifM , BudniokAet al.Metal-dependent cytotoxic and kinesin spindle protein inhibitory activity of Ru, Os, Rh, and Ir half-sandwich complexes of ispinesib-derived ligands. Inorg. Chem.59, 14879–14890 (2020).
  • JiangC , YouQ. Kinesin spindle protein inhibitors in cancer: a patent review (2008–present). Expert Opin. Ther. Pat.23, 1547–1560 (2013).
  • YangL , JiangC , LiuFet al.Cloning, enzyme characterization of recombinant human Eg5 and the development of a new inhibitor. Biol. Pharm. Bull.31, 1397–1402 (2008).
  • FuRG , YouQD , YangL , WuWT , JiangC , XuXL. Design, synthesis and bioevaluation of dihydropyrazolo[3,4-b]pyridine and benzo[4,5]imidazo[1,2-a]pyrimidine compounds as dual KSP and Aurora-A kinase inhibitors for anti-cancer agents. Bioorg. Med. Chem.18, 8035–8043 (2010).