Discovery of Polo-like Kinase 4 Inhibitors for the Treatment of Cancer:
A Mini Patent Review

Yang      Shu; Yajing      Liu; Shirong      Bian; Zhouling      Xie; Chenzhong      Liao
doi:10.2174/1381612828666220603124115
Abstract

Polo-like kinase 4 (PLK4), a serine/threonine kinase, is a member of the PLK family. As a key regulator of the cell cycle, PLK4 controls centrosome duplication and mitosis. Abnormal PLK4’s function can induce centrosome amplification, leading to tumorigenesis, therefore, PLK4 has been regarded as a promising target for cancer therapy, and PLK4 inhibitors have potentials to treat multiple cancers and other PLK4-associated human disorders, such as myelodysplastic syndrome. In addition, PLK4 may function as a DNA-damage sensitizer, therefore improving the efficacy of chemotherapy. To date, some small-molecule inhibitors with different chemical scaffolds targeting PLK4 have been reported, among which, CFI-400945 has entered clinical trials for the treatment of various solid tumors, myeloid leukemia, and myelodysplastic syndrome. In this review, the structure and biological functions of PLK4 with other homologous PLKs are compared; the roles of PLK4 in different cancers are reviewed; and PLK4 inhibitors disclosed in patent or literature are summarized. Used alone or in combination with other anticancer drugs in preclinical and clinical studies, PLK4 inhibitors have shown significant efficacy in the treatment of different cancers, demonstrating that PLK4 could be a critical target for cancer diagnosis and therapy. However, our understanding of PLK4 is still limited, and novel mechanisms of PLK4 should be identified in future studies.
Keywords: Polo-like kinases, PLK4, centrosome amplification, cancer, inhibitor, patent.
« Previous Next »
Graphical Abstract

[1]
Attwood, M.M.; Fabbro, D.; Sokolov, A.V.; Knapp, S.; Schiöth, H.B. Trends in kinase drug discovery: Targets, indications and inhibitor design. Nat. Rev. Drug Discov.,  2021, 20(11), 839-861.
 [http://dx.doi.org/10.1038/s41573-021-00252-y] [PMID:  34354255]

[2]
Xie, Z.; Yang, X.; Duan, Y.; Han, J.; Liao, C. Small-molecule kinase inhibitors for the treatment of nononcologic diseases. J. Med. Chem.,  2021, 64(3), 1283-1345.
 [http://dx.doi.org/10.1021/acs.jmedchem.0c01511] [PMID:  33481605]

[3]
Ayala-Aguilera, C.C.; Valero, T.; Lorente-Macías, Á.; Baillache, D.J.; Croke, S.; Unciti-Broceta, A. Small molecule kinase inhibitor drugs (1995-2021): Medical indication, pharmacology, and synthesis. J. Med. Chem.,  2022, 65(2), 1047-1131.
 [http://dx.doi.org/10.1021/acs.jmedchem.1c00963] [PMID:  34624192]

[4]
Liao, C.; Yao, R. Diversity evolution and jump of Polo-like kinase 1 inhibitors. Sci. China Chem.,  2013, 56(10), 1392-1401.
 [http://dx.doi.org/10.1007/s11426-013-4963-0]

[5]
Zitouni, S.; Nabais, C.; Jana, S.C.; Guerrero, A.; Bettencourt-Dias, M. Polo-like kinases: Structural variations lead to multiple functions. Nat. Rev. Mol. Cell Biol.,  2014, 15(7), 433-452.
 [http://dx.doi.org/10.1038/nrm3819] [PMID:  24954208]

[6]
Lee, K.S.; Burke, T.R., Jr; Park, J.E.; Bang, J.K.; Lee, E. Recent advances and new strategies in targeting Plk1 for anticancer therapy. Trends Pharmacol. Sci.,  2015, 36(12), 858-877.
 [http://dx.doi.org/10.1016/j.tips.2015.08.013] [PMID:  26478211]

[7]
Hoffmann, I. Role of polo-like kinases Plk1 and Plk4 in the initiation of centriole duplication-impact on cancer. Cells,  2022, 11(5), 786.
 [http://dx.doi.org/10.3390/cells11050786] [PMID:  35269408]

[8]
Zhang, X.; Wei, C.; Liang, H.; Han, L. Polo-like kinase 4's critical role in cancer development and strategies for Plk4-targeted therapy. Front. Oncol.,  2021, 11, 587554.
 [http://dx.doi.org/10.3389/fonc.2021.587554] [PMID:  33777739]

[9]
Zhao, Y.; Wang, X. PLK4: A promising target for cancer therapy. J. Cancer Res. Clin. Oncol.,  2019, 145(10), 2413-2422.
 [http://dx.doi.org/10.1007/s00432-019-02994-0] [PMID:  31492983]

[10]
Shakeel, I.; Basheer, N.; Hasan, G.M.; Afzal, M.; Hassan, M.I. Polo-like Kinase 1 as an emerging drug target: Structure, function and therapeutic implications. J. Drug Target.,  2021, 29(2), 168-184.
 [http://dx.doi.org/10.1080/1061186X.2020.1818760] [PMID:  32886539]

[11]
Lee, J.S.; Lee, Y.; André, E.A.; Lee, K.J.; Nguyen, T.; Feng, Y.; Jia, N.; Harris, B.T.; Burns, M.P.; Pak, D.T.S. Inhibition of Polo-like kinase 2 ameliorates pathogenesis in Alzheimer’s disease model mice. PLoS One,  2019, 14(7), e0219691.
 [http://dx.doi.org/10.1371/journal.pone.0219691] [PMID:  31306446]

[12]
Li, W.X.; Li, G.H.; Tong, X.; Yang, P.P.; Huang, J.F.; Xu, L.; Dai, S.X. Systematic metabolic analysis of potential target, therapeutic drug, diagnostic method and animal model applicability in three neurodegenerative diseases. Aging (Albany NY),  2020, 12(10), 9882-9914.
 [http://dx.doi.org/10.18632/aging.103253] [PMID:  32461378]

[13]
Hong, C.T.; Chen, K.Y.; Wang, W.; Chiu, J.Y.; Wu, D.; Chao, T.Y.; Hu, C.J.; Chau, K.D.; Bamodu, O.A. Insulin resistance promotes Parkinson’s disease through aberrant expression of α-synuclein, mitochondrial dysfunction, and deregulation of the polo-like kinase 2 signaling. Cells,  2020, 9(3), 740.
 [http://dx.doi.org/10.3390/cells9030740] [PMID:  32192190]

[14]
Bahassi, M.; Hennigan, R.F.; Myer, D.L.; Stambrook, P.J. CDC25C phosphorylation on serine 191 by Plk3 promotes its nuclear translocation. Oncogene,  2004, 23(15), 2658-2663.
 [http://dx.doi.org/10.1038/sj.onc.1207425] [PMID:  14968113]

[15]
Xu, D.; Dai, W.; Li, C. Polo-like kinase 3, hypoxic responses, and tumorigenesis. Cell Cycle,  2017, 16(21), 2032-2036.
 [http://dx.doi.org/10.1080/15384101.2017.1373224] [PMID:  28857653]

[16]
Helmke, C.; Becker, S.; Strebhardt, K. The role of Plk3 in oncogenesis. Oncogene,  2016, 35(2), 135-147.
 [http://dx.doi.org/10.1038/onc.2015.105] [PMID:  25915845]

[17]
de Cárcer, G.; Manning, G.; Malumbres, M. From Plk1 to Plk5: Functional evolution of polo-like kinases. Cell Cycle,  2011, 10(14), 2255-2262.
 [http://dx.doi.org/10.4161/cc.10.14.16494] [PMID:  21654194]

[18]
de Cárcer, G.; Escobar, B.; Higuero, A.M.; García, L.; Ansón, A.; Pérez, G.; Mollejo, M.; Manning, G.; Meléndez, B.; Abad-Rodríguez, J.; Malumbres, M. Plk5, a polo box domain-only protein with specific roles in neuron differentiation and glioblastoma suppression. Mol. Cell. Biol.,  2011, 31(6), 1225-1239.
 [http://dx.doi.org/10.1128/MCB.00607-10] [PMID:  21245385]

[19]
Andrysik, Z.; Bernstein, W.Z.; Deng, L.; Myer, D.L.; Li, Y.Q.; Tischfield, J.A.; Stambrook, P.J.; Bahassi, M. The novel mouse Polo-like kinase 5 responds to DNA damage and localizes in the nucleolus. Nucleic Acids Res.,  2010, 38(9), 2931-2943.
 [http://dx.doi.org/10.1093/nar/gkq011] [PMID:  20100802]

[20]
Maniswami, R.R.; Prashanth, S.; Karanth, A.V.; Koushik, S.; Govindaraj, H.; Mullangi, R.; Rajagopal, S.; Jegatheesan, S.K. PLK4: A link between centriole biogenesis and cancer. Expert Opin. Ther. Targets,  2018, 22(1), 59-73.
 [http://dx.doi.org/10.1080/14728222.2018.1410140] [PMID:  29171762]

[21]
Garvey, D.R.; Chhabra, G.; Ndiaye, M.A.; Ahmad, N. Role of Polo-Like Kinase 4 (PLK4) in epithelial cancers and recent progress in its small molecule targeting for Cancer management. Mol. Cancer Ther.,  2021, 20(4), 632-640.
 [http://dx.doi.org/10.1158/1535-7163.MCT-20-0741] [PMID:  33402398]

[22]
Moyer, T.C.; Clutario, K.M.; Lambrus, B.G.; Daggubati, V.; Holland, A.J. Binding of STIL to Plk4 activates kinase activity to promote centriole assembly. J. Cell Biol.,  2015, 209(6), 863-878.
 [http://dx.doi.org/10.1083/jcb.201502088] [PMID:  26101219]

[23]
Arquint, C.; Gabryjonczyk, A.M.; Imseng, S.; Böhm, R.; Sauer, E.; Hiller, S.; Nigg, E.A.; Maier, T. STIL binding to Polo-box 3 of PLK4 regulates centriole duplication. eLife,  2015, 4, e07888.
 [http://dx.doi.org/10.7554/eLife.07888] [PMID:  26188084]

[24]
Klebba, J.E.; Buster, D.W.; McLamarrah, T.A.; Rusan, N.M.; Rogers, G.C. Autoinhibition and relief mechanism for Polo-like kinase 4. Proc. Natl. Acad. Sci. USA,  2015, 112(7), E657-E666.
 [http://dx.doi.org/10.1073/pnas.1417967112] [PMID:  25646492]

[25]
Press, M.F.; Xie, B.; Davenport, S.; Zhou, Y.; Guzman, R.; Nolan, G.P.; O’Brien, N.; Palazzolo, M.; Mak, T.W.; Brugge, J.S.; Slamon, D.J. Role for polo-like kinase 4 in mediation of cytokinesis. Proc. Natl. Acad. Sci. USA,  2019, 116(23), 11309-11318.
 [http://dx.doi.org/10.1073/pnas.1818820116] [PMID:  31097597]

[26]
Raab, C.A.; Raab, M.; Becker, S.; Strebhardt, K. Non-mitotic functions of polo-like kinases in cancer cells. Biochim. Biophys. Acta Rev. Cancer,  2021, 1875(1), 188467.
 [http://dx.doi.org/10.1016/j.bbcan.2020.188467] [PMID:  33171265]

[27]
Jaiswal, S.; Singh, P. Centrosome dysfunction in human diseases. Semin. Cell Dev. Biol.,  2021, 110, 113-122.
 [http://dx.doi.org/10.1016/j.semcdb.2020.04.019] [PMID:  32409142]

[28]
Zhao, H.; Yang, S.; Chen, Q.; Duan, X.; Li, G.; Huang, Q.; Zhu, X.; Yan, X. Cep57 and Cep57l1 function redundantly to recruit the Cep63-Cep152 complex for centriole biogenesis. J. Cell Sci.,  2020, 133(13), jcs241836.
 [http://dx.doi.org/10.1242/jcs.241836] [PMID:  32503940]

[29]
Sonnen, K.F.; Gabryjonczyk, A.M.; Anselm, E.; Stierhof, Y.D.; Nigg, E.A. Human Cep192 and Cep152 cooperate in Plk4 recruitment and centriole duplication. J. Cell Sci.,  2013, 126(Pt 14), 3223-3233.
 [http://dx.doi.org/10.1242/jcs.129502] [PMID:  23641073]

[30]
Kim, T.S.; Park, J.E.; Shukla, A.; Choi, S.; Murugan, R.N.; Lee, J.H.; Ahn, M.; Rhee, K.; Bang, J.K.; Kim, B.Y.; Loncarek, J.; Erikson, R.L.; Lee, K.S. Hierarchical recruitment of Plk4 and regulation of centriole biogenesis by two centrosomal scaffolds, Cep192 and Cep152. Proc. Natl. Acad. Sci. USA,  2013, 110(50), E4849-E4857.
 [http://dx.doi.org/10.1073/pnas.1319656110] [PMID:  24277814]

[31]
Moyer, T.C.; Holland, A.J. PLK4 promotes centriole duplication by phosphorylating STIL to link the procentriole cartwheel to the micro-tubule wall. eLife,  2019, 8, e46054.
 [http://dx.doi.org/10.7554/eLife.46054] [PMID:  31115335]

[32]
Chi, W.; Wang, G.; Xin, G.; Jiang, Q.; Zhang, C. PLK4-phosphorylated NEDD1 facilitates cartwheel assembly and centriole biogenesis initiations. J. Cell Biol.,  2021, 220(1), e202002151.
 [http://dx.doi.org/10.1083/jcb.202002151] [PMID:  33351100]

[33]
Mittal, K.; Kaur, J.; Jaczko, M.; Wei, G.; Toss, M.S.; Rakha, E.A.; Janssen, E.A.M.; Søiland, H.; Kucuk, O.; Reid, M.D.; Gupta, M.V.; Aneja, R. Centrosome amplification: A quantifiable cancer cell trait with prognostic value in solid malignancies. Cancer Metastasis Rev.,  2021, 40(1), 319-339.
 [http://dx.doi.org/10.1007/s10555-020-09937-z] [PMID:  33106971]

[34]
Kazazian, K.; Haffani, Y.; Ng, D.; Lee, C.M.M.; Johnston, W.; Kim, M.; Xu, R.; Pacholzyk, K.; Zih, F.S.; Tan, J.; Smrke, A.; Pollett, A.; Wu, H.S.; Swallow, C.J. FAM46C/TENT5C functions as a tumor suppressor through inhibition of Plk4 activity. Commun. Biol.,  2020, 3(1), 448.
 [http://dx.doi.org/10.1038/s42003-020-01161-3] [PMID:  32807875]

[35]
Liu, Y.; Kim, J.; Philip, R.; Sridhar, V.; Chandrashekhar, M.; Moffat, J.; van Breugel, M.; Pelletier, L. Direct interaction between CEP85 and STIL mediates PLK4-driven directed cell migration. J. Cell Sci.,  2020, 133(8), jcs238352.
 [http://dx.doi.org/10.1242/jcs.238352] [PMID:  32107292]

[36]
Fontana, F.; Anselmi, M.; Limonta, P. Molecular mechanisms and genetic alterations in prostate cancer: From diagnosis to targeted therapy. Cancer Lett.,  2022, 534, 215619.
 [http://dx.doi.org/10.1016/j.canlet.2022.215619] [PMID:  35276289]

[37]
Singh, C.K.; Denu, R.A.; Nihal, M.; Shabbir, M.; Garvey, D.R.; Huang, W.; Iczkowski, K.A.; Ahmad, N. PLK4 is upregulated in prostate cancer and its inhibition reduces centrosome amplification and causes senescence. Prostate,  2022, 82(9), 957-969.
 [http://dx.doi.org/10.1002/pros.24342] [PMID:  35333404]

[38]
Mittal, K.; Kaur, J.; Sharma, S.; Sharma, N.; Wei, G.; Choudhary, I.; Imhansi-Jacob, P.; Maganti, N.; Pawar, S.; Rida, P.; Toss, M.S.; Ales-kandarany, M.; Janssen, E.A.; Soiland, H.; Gupta, M.V.; Reid, M.D.; Rakha, E.A.; Aneja, R. Hypoxia drives centrosome amplification in cancer cells via HIF1α-dependent induction of polo-like Kinase 4. Mol. Cancer Res.,  2022, 20(4), 596-606.
 [http://dx.doi.org/10.1158/1541-7786.MCR-20-0798] [PMID:  34933912]

[39]
Korzeniewski, N.; Hohenfellner, M.; Duensing, S. CAND1 promotes PLK4-mediated centriole overduplication and is frequently disrupted in prostate cancer. Neoplasia,  2012, 14(9), 799-806.
 [http://dx.doi.org/10.1593/neo.12580] [PMID:  23019411]

[40]
Ward, A.; Sivakumar, G.; Kanjeekal, S.; Hamm, C.; Labute, B.C.; Shum, D.; Hudson, J.W. The deregulated promoter methylation of the Polo-like kinases as a potential biomarker in hematological malignancies. Leuk. Lymphoma,  2015, 56(7), 2123-2133.
 [http://dx.doi.org/10.3109/10428194.2014.971407] [PMID:  25347426]

[41]
Li, S.; Wang, C.; Wang, W.; Liu, W.; Zhang, G. Abnormally high expression of POLD1, MCM2, and PLK4 promotes relapse of acute lymphoblastic leukemia. Medicine (Baltimore),  2018, 97(20), e10734.
 [http://dx.doi.org/10.1097/MD.0000000000010734] [PMID:  29768346]

[42]
Rahmani, F.; Tadayyon Tabrizi, A.; Hashemian, P.; Alijannejad, S.; Rahdar, H.A.; Ferns, G.A.; Hassanian, S.M.; Shahidsales, S.; Avan, A. Role of regulatory miRNAs of the Wnt/β-catenin signaling pathway in tumorigenesis of breast cancer. Gene,  2020, 754, 144892.
 [http://dx.doi.org/10.1016/j.gene.2020.144892] [PMID:  32534060]

[43]
Li, Z.; Dai, K.; Wang, C.; Song, Y.; Gu, F.; Liu, F.; Fu, L. Expression of polo-like Kinase 4(PLK4) in breast cancer and its response to taxane-based neoadjuvant chemotherapy. J. Cancer,  2016, 7(9), 1125-1132.
 [http://dx.doi.org/10.7150/jca.14307] [PMID:  27326256]

[44]
Lei, Q.; Xiong, L.; Xia, Y.; Feng, Z.; Gao, T.; Wei, W.; Song, X.; Ye, T.; Wang, N.; Peng, C.; Li, Z.; Liu, Z.; Yu, L. YLT-11, a novel PLK4 inhibitor, inhibits human breast cancer growth via inducing maladjusted centriole duplication and mitotic defect. Cell Death Dis.,  2018, 9(11), 1066.
 [http://dx.doi.org/10.1038/s41419-018-1071-2] [PMID:  30337519]

[45]
Parsyan, A.; Cruickshank, J.; Hodgson, K.; Wakeham, D.; Pellizzari, S.; Bhat, V.; Cescon, D.W. Anticancer effects of radiation therapy combined with Polo-Like Kinase 4 (PLK4) inhibitor CFI-400945 in triple negative breast cancer. Breast,  2021, 58, 6-9.
 [http://dx.doi.org/10.1016/j.breast.2021.03.011] [PMID:  33866248]

[46]
Tian, X.; Zhou, D.; Chen, L.; Tian, Y.; Zhong, B.; Cao, Y.; Dong, Q.; Zhou, M.; Yan, J.; Wang, Y.; Qiu, Y.; Zhang, L.; Li, Z.; Wang, H.; Wang, D.; Ying, G.; Zhao, Q. Polo-like kinase 4 mediates epithelial-mesenchymal transition in neuroblastoma via PI3K/Akt signaling pathway. Cell Death Dis.,  2018, 9(2), 54.
 [http://dx.doi.org/10.1038/s41419-017-0088-2] [PMID:  29352113]

[47]
Wang, J.; Ren, D.; Sun, Y.; Xu, C.; Wang, C.; Cheng, R.; Wang, L.; Jia, G.; Ren, J.; Ma, J.; Tu, Y.; Ji, H. Inhibition of PLK4 might enhance the anti-tumour effect of bortezomib on glioblastoma via PTEN/PI3K/AKT/mTOR signalling pathway. J. Cell. Mol. Med.,  2020, 24(7), 3931-3947.
 [http://dx.doi.org/10.1111/jcmm.14996] [PMID:  32126150]

[48]
Sredni, S.T.; Bailey, A.W.; Suri, A.; Hashizume, R.; He, X.; Louis, N.; Gokirmak, T.; Piper, D.R.; Watterson, D.M.; Tomita, T. Inhibition of polo-like kinase 4 (PLK4): A new therapeutic option for rhabdoid tumors and pediatric medulloblastoma. Oncotarget,  2017, 8(67), 111190-111212.
 [http://dx.doi.org/10.18632/oncotarget.22704] [PMID:  29340047]

[49]
Pu, J.T.; Hu, Z.; Zhang, D.G.; Zhang, T.; He, K.M.; Dai, T.Y. MiR-654-3p suppresses non-small cell lung cancer tumourigenesis by inhi-biting PLK4. OncoTargets Ther.,  2020, 13, 7997-8008.
 [http://dx.doi.org/10.2147/OTT.S258616] [PMID:  32884289]

[50]
Liu, L.; Zhang, C.Z.; Cai, M.; Fu, J.; Chen, G.G.; Yun, J. Downregulation of polo-like kinase 4 in hepatocellular carcinoma associates with poor prognosis. PLoS One,  2012, 7(7), e41293.
 [http://dx.doi.org/10.1371/journal.pone.0041293] [PMID:  22829937]

[51]
Abreu, P.; Ivanics, T.; Jiang, K.; Chen, K.; E Hansen, B.; Sapisochin, G.; Ghanekar, A. Novel biomarker for hepatocellular carcinoma: High tumoral PLK-4 expression is associated with better prognosis in patients without microvascular invasion. HPB (Oxford),  2021, 23(3), 359-366.
 [http://dx.doi.org/10.1016/j.hpb.2020.07.003] [PMID:  32800449]

[52]
Meng, L.; Zhou, Y.; Ju, S.; Han, J.; Song, C.; Kong, J.; Wu, Y.; Lu, S.; Xu, J.; Yuan, W.; Zhang, E.; Wang, C.; Hu, Z.; Gu, Y.; Luo, R.; Wang, X. A cis-eQTL genetic variant in PLK4 confers high risk of hepatocellular carcinoma. Cancer Med.,  2019, 8(14), 6476-6484.
 [http://dx.doi.org/10.1002/cam4.2487] [PMID:  31489978]

[53]
Bao, J.; Yu, Y.; Chen, J.; He, Y.; Chen, X.; Ren, Z.; Xue, C.; Liu, L.; Hu, Q.; Li, J.; Cui, G.; Sun, R. MiR-126 negatively regulates PLK-4 to impact the development of hepatocellular carcinoma via ATR/CHEK1 pathway. Cell Death Dis.,  2018, 9(10), 1045.
 [http://dx.doi.org/10.1038/s41419-018-1020-0] [PMID:  30315225]

[54]
Zhang, N.; Hu, X.; Du, Y.; Du, J. The role of miRNAs in colorectal cancer progression and chemoradiotherapy. Biomed. Pharmacother.,  2021, 134, 111099.
 [http://dx.doi.org/10.1016/j.biopha.2020.111099] [PMID:  33338745]

[55]
Liao, Z.; Zhang, H.; Fan, P.; Huang, Q.; Dong, K.; Qi, Y.; Song, J.; Chen, L.; Liang, H.; Chen, X.; Zhang, Z.; Zhang, B. High PLK4 expression promotes tumor progression and induces epithelial mesenchymal transition by regulating the Wnt/β catenin signaling pathway in colorectal cancer. Int. J. Oncol.,  2019, 54(2), 479-490.
 [http://dx.doi.org/10.3892/ijo.2018.4659] [PMID:  30570110]

[56]
Yang, Z.; Sun, H.; Ma, W.; Wu, K.; Peng, G.; Ou, T.; Wu, S. Down-regulation of Polo-like kinase 4 (PLK4) induces G1 arrest via activa-tion of the p38/p53/p21 signaling pathway in bladder cancer. FEBS Open Bio,  2021, 11(9), 2631-2646.
 [http://dx.doi.org/10.1002/2211-5463.13262] [PMID:  34342940]

[57]
Zhao, Y.; Yang, J.; Liu, J.; Cai, Y.; Han, Y.; Hu, S.; Ren, S.; Zhou, X.; Wang, X. Inhibition of Polo-like kinase 4 induces mitotic defects and DNA damage in diffuse large B-cell lymphoma. Cell Death Dis.,  2021, 12(7), 640.
 [http://dx.doi.org/10.1038/s41419-021-03919-x] [PMID:  34162828]

[58]
Kressin, M.; Fietz, D.; Becker, S.; Strebhardt, K. Modelling the functions of polo-like kinases in mice and their applications as cancer targets with a special focus on Ovarian Cancer. Cells,  2021, 10(5), 1176.
 [http://dx.doi.org/10.3390/cells10051176] [PMID:  34065956]

[59]
Kelleher, F.C.; Kroes, J.; Lewin, J. Targeting the centrosome and polo-like kinase 4 in osteosarcoma. Carcinogenesis,  2019, 40(4), 493-499.
 [http://dx.doi.org/10.1093/carcin/bgy175] [PMID:  30508038]

[60]
Brenchley, G.; Charrier, J.-D.; Durrant, S.; Knegtel, R.; Ramaya, S.; Sadiq, S. Thiophene-carboxamides useful as inhibitors of protein kinases. W.O. Patent 2007139795A1, May 22, 2007.

[61]
Feger, D. Use of indolocarbazole imides as protein kinase inhibitors for the treatment of hematologic and solid tumors. W.O. Patent 2009047216A2, April 16, 2009.

[62]
Diels, G.S.M.; Ten Holte, P.; Freyne, E.J.E.; Grand-Perret, T.A.R.; Van Emelen, K.; Embrechts, W.C.J.; Bonnet, P.G.A. Pyrrolopyrimidine derivatives as polo-like kinase inhibitors and their preparation, pharmaceutical compositions and use in the treatment of cancer. W.O. Patent 2009016132A1, February 5, 2009.

[63]
Buijnsters, P.J.J.A.; Verdonck, M.G.C.; Van Emelen, K.; Bonnet, P.G.A. 4-Aryl-2-anilinopyrimidines as PLK kinase inhibitors and their preparation, pharmaceutical compositions and use in the treatment of kinase-mediated diseases. W.O. Patent 2009112439A1, September 17, 2009.

[64]
Pauls, H.W.; Forrest, B.T.; Laufer, R.; Feher, M.; Sampson, P.B.; Pan, G. Preparation of indazolyl, benzimidazolyl, benzotriazolyl substituted indolin-2-one derivatives as kinase inhibitors useful in the treatment of cancer. W.O. Patent 2009079767A1, July 2, 2009.

[65]
Sampson, P.B.; Liu, Y.; Li, S.-W.; Forrest, B.T.; Pauls, H.W.; Edwards, L.G.; Feher, M.; Patel, N.K.B.; Laufer, R.; Pan, G. (1HIndazol- 6-yl)spiro[cyclopropane-1,3'-indolin]-2'-one derivatives as protein kinase inhibitors and their preparation and use for the treatment of cancer. W.O. Patent 2011123946A1, October 13, 2011.

[66]
Pauls, H.W.; Laufer, R.; Liu, Y.; Li, S.-W.; Forrest, B.T.; Lang, Y.; Patel, N.K.B.; Edwards, L.G.; Ng, G.; Sampson, P.B.; Feher, M.; Awrey, D.E. Indazole compounds as kinase inhibitors and their preparation and method of treating cancer. W.O. Patent 2013053051A1, April 18, 2013.

[67]
Liu, Z.H.; Lei, Q.; Wei, W.; Xiong, L.; Shi, Y.J.; Yan, G.Y.; Gao, C.; Ye, T.H.; Wang, N.Y.; Yu, L.T. Synthesis and biological evaluation of (E)-4-(3-arylvinyl-1H-indazol-6-yl) pyrimidin-2-amine derivatives as PLK4 inhibitors for the treatment of breast cancer. RSC Advances,  2017, 7(44), 27737-27746.
 [http://dx.doi.org/10.1039/C7RA02518A]

[68]
Hu-Lowe, D.D.; Zou, H.Y.; Grazzini, M.L.; Hallin, M.E.; Wickman, G.R.; Amundson, K.; Chen, J.H.; Rewolinski, D.A.; Yamazaki, S.; Wu, E.Y.; McTigue, M.A.; Murray, B.W.; Kania, R.S.; O’Connor, P.; Shalinsky, D.R.; Bender, S.L. Nonclinical antiangiogenesis and antitumor activities of axitinib (AG-013736), an oral, potent, and selective inhibitor of vascular endothelial growth factor receptor tyrosine kinases 1, 2, 3. Clin. Cancer Res.,  2008, 14(22), 7272-7283.
 [http://dx.doi.org/10.1158/1078-0432.CCR-08-0652] [PMID:  19010843]

[69]
Rössler, J.; Monnet, Y.; Farace, F.; Opolon, P.; Daudigeos-Dubus, E.; Bourredjem, A.; Vassal, G.; Geoerger, B. The selective VEGFR1-3 inhibitor axitinib (AG-013736) shows antitumor activity in human neuroblastoma xenografts. Int. J. Cancer,  2011, 128(11), 2748-2758.
 [http://dx.doi.org/10.1002/ijc.25611] [PMID:  20715103]

[70]
Liu, J.J.; Higgins, B.; Ju, G.; Kolinsky, K.; Luk, K.C.; Packman, K.; Pizzolato, G.; Ren, Y.; Thakkar, K.; Tovar, C.; Zhang, Z.; Wovkulich, P.M. Discovery of a highly potent, orally active mitosis/angiogenesis inhibitor r1530 for the treatment of solid tumors. ACS Med. Chem. Lett.,  2013, 4(2), 259-263.
 [http://dx.doi.org/10.1021/ml300351e] [PMID:  24900658]

[71]
Gahman, T.; Shiau, A. K. Preparation of substituted pyrimidinamines as PLK4 inhibitors for treating cancer. W.O. Patent 2016166604A1, October 20, 2016.

[72]
Wong, Y.L.; Anzola, J.V.; Davis, R.L.; Yoon, M.; Motamedi, A.; Kroll, A.; Seo, C.P.; Hsia, J.E.; Kim, S.K.; Mitchell, J.W.; Mitchell, B.J.; Desai, A.; Gahman, T.C.; Shiau, A.K.; Oegema, K. Cell biology. Reversible centriole depletion with an inhibitor of Polo-like kinase 4. Science,  2015, 348(6239), 1155-1160.
 [http://dx.doi.org/10.1126/science.aaa5111] [PMID:  25931445]

[73]
Veitch, Z.W.; Cescon, D.W.; Denny, T.; Yonemoto, L.M.; Fletcher, G.; Brokx, R.; Sampson, P.; Li, S.W.; Pugh, T.J.; Bruce, J.; Bray, M.R.; Slamon, D.J.; Mak, T.W.; Wainberg, Z.A.; Bedard, P.L. Safety and tolerability of CFI-400945, a first-in-class, selective PLK4 inhibitor in advanced solid tumours: A phase 1 dose-escalation trial. Br. J. Cancer,  2019, 121(4), 318-324.
 [http://dx.doi.org/10.1038/s41416-019-0517-3] [PMID:  31303643]
Rights & Permissions Print Cite
Article Metrics
10
Journal Information
For Authors
For Editors
For Reviewers
Explore Articles
Open Access
Open Access Articles
For Visitors
DOI https://dx.doi.org/10.2174/1381612828666220603124115	Print ISSN 1389-5575
Publisher Name Bentham Science Publisher	Online ISSN 1875-5607
Mini-Reviews in Medicinal Chemistry

Discovery of Polo-like Kinase 4 Inhibitors for the Treatment of Cancer: A Mini Patent Review

Abstract Play Pause

Graphical Abstract

Related Journals

Related Books

Abstract
