Target Information
| Target General Information | Top | |||||
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| Target ID |
T40694
(Former ID: TTDC00160)
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| Target Name |
Polo-like kinase 1 (PLK1)
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| Synonyms |
Serine/threonine-protein kinase PLK1; Serine/threonine-protein kinase 13; Serine-threonine protein kinase 13; STPK13; Plk1; PLK-1; PLK; Mitoticserine-threonine kinase polo-like kinase 1
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| Gene Name |
PLK1
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| Target Type |
Clinical trial target
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[1] | ||||
| Disease | [+] 3 Target-related Diseases | + | ||||
| 1 | Acute myeloid leukaemia [ICD-11: 2A60] | |||||
| 2 | Myelodysplastic syndrome [ICD-11: 2A37] | |||||
| 3 | Solid tumour/cancer [ICD-11: 2A00-2F9Z] | |||||
| Function |
Polo-like kinase proteins acts by binding and phosphorylating proteins are that already phosphorylated on a specific motif recognized by the POLO box domains. Phosphorylates BORA, BUB1B/BUBR1, CCNB1, CDC25C, CEP55, ECT2, ERCC6L, FBXO5/EMI1, FOXM1, KIF20A/MKLP2, CENPU, NEDD1, NINL, NPM1, NUDC, PKMYT1/MYT1, KIZ, PPP1R12A/MYPT1, PRC1, RACGAP1/CYK4, SGO1, STAG2/SA2, TEX14, TOPORS, p73/TP73, TPT1, WEE1 and HNRNPU. Plays a key role in centrosome functions and the assembly of bipolar spindles by phosphorylating KIZ, NEDD1 and NINL. NEDD1 phosphorylation promotes subsequent targeting of the gamma-tubulin ring complex (gTuRC) to the centrosome, an important step for spindle formation. Phosphorylation of NINL component of the centrosome leads to NINL dissociation from other centrosomal proteins. Involved in mitosis exit and cytokinesis by phosphorylating CEP55, ECT2, KIF20A/MKLP2, CENPU, PRC1 and RACGAP1. Recruited at the central spindle by phosphorylating and docking PRC1 and KIF20A/MKLP2; creates its own docking sites on PRC1 and KIF20A/MKLP2 by mediating phosphorylation of sites subsequently recognized by the POLO box domains. Phosphorylates RACGAP1, thereby creating a docking site for the Rho GTP exchange factor ECT2 that is essential for the cleavage furrow formation. Promotes the central spindle recruitment of ECT2. Plays a central role in G2/M transition of mitotic cell cycle by phosphorylating CCNB1, CDC25C, FOXM1, CENPU, PKMYT1/MYT1, PPP1R12A/MYPT1 and WEE1. Part of a regulatory circuit that promotes the activation of CDK1 by phosphorylating the positive regulator CDC25C and inhibiting the negative regulators WEE1 and PKMYT1/MYT1. Also acts by mediating phosphorylation of cyclin-B1 (CCNB1) on centrosomes in prophase. Phosphorylates FOXM1, a key mitotic transcription regulator, leading to enhance FOXM1 transcriptional activity. Involved in kinetochore functions and sister chromatid cohesion by phosphorylating BUB1B/BUBR1, FBXO5/EMI1 and STAG2/SA2. PLK1 is high on non-attached kinetochores suggesting a role of PLK1 in kinetochore attachment or in spindle assembly checkpoint (SAC) regulation. Required for kinetochore localization of BUB1B. Regulates the dissociation of cohesin from chromosomes by phosphorylating cohesin subunits such as STAG2/SA2. Phosphorylates SGO1: required for spindle pole localization of isoform 3 of SGO1 and plays a role in regulating its centriole cohesion function. Mediates phosphorylation of FBXO5/EMI1, a negative regulator of the APC/C complex during prophase, leading to FBXO5/EMI1 ubiquitination and degradation by the proteasome. Acts as a negative regulator of p53 family members: phosphorylates TOPORS, leading to inhibit the sumoylation of p53/TP53 and simultaneously enhance the ubiquitination and subsequent degradation of p53/TP53. Phosphorylates the transactivation domain of the transcription factor p73/TP73, leading to inhibit p73/TP73-mediated transcriptional activation and pro-apoptotic functions. Phosphorylates BORA, and thereby promotes the degradation of BORA. Contributes to the regulation of AURKA function. Also required for recovery after DNA damage checkpoint and entry into mitosis. Phosphorylates MISP, leading to stabilization of cortical and astral microtubule attachments required for proper spindle positioning. Together with MEIKIN, acts as a regulator of kinetochore function during meiosis I: required both for mono-orientation of kinetochores on sister chromosomes and protection of centromeric cohesin from separase-mediated cleavage. Phosphorylates CEP68 and is required for its degradation. Regulates nuclear envelope breakdown during prophase by phosphorylating DCTN1 resulting in its localization in the nuclear envelope. Phosphorylates the heat shock transcription factor HSF1, promoting HSF1 nuclear translocation upon heat shock. Phosphorylates HSF1 also in the early mitotic period; this phosphorylation regulates HSF1 localization to the spindle pole, the recruitment of the SCF(BTRC) ubiquitin ligase complex induicing HSF1 degradation, and hence mitotic progression. Regulates mitotic progression by phosphorylating RIOK2. Serine/threonine-protein kinase that performs several important functions throughout M phase of the cell cycle, including the regulation of centrosome maturation and spindle assembly, the removal of cohesins from chromosome arms, the inactivation of anaphase-promoting complex/cyclosome (APC/C) inhibitors, and the regulation of mitotic exit and cytokinesis.
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| BioChemical Class |
Kinase
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| UniProt ID | ||||||
| EC Number |
EC 2.7.11.21
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| Sequence |
MSAAVTAGKLARAPADPGKAGVPGVAAPGAPAAAPPAKEIPEVLVDPRSRRRYVRGRFLG
KGGFAKCFEISDADTKEVFAGKIVPKSLLLKPHQREKMSMEISIHRSLAHQHVVGFHGFF EDNDFVFVVLELCRRRSLLELHKRRKALTEPEARYYLRQIVLGCQYLHRNRVIHRDLKLG NLFLNEDLEVKIGDFGLATKVEYDGERKKTLCGTPNYIAPEVLSKKGHSFEVDVWSIGCI MYTLLVGKPPFETSCLKETYLRIKKNEYSIPKHINPVAASLIQKMLQTDPTARPTINELL NDEFFTSGYIPARLPITCLTIPPRFSIAPSSLDPSNRKPLTVLNKGLENPLPERPREKEE PVVRETGEVVDCHLSDMLQQLHSVNASKPSERGLVRQEEAEDPACIPIFWVSKWVDYSDK YGLGYQLCDNSVGVLFNDSTRLILYNDGDSLQYIERDGTESYLTVSSHPNSLMKKITLLK YFRNYMSEHLLKAGANITPREGDELARLPYLRTWFRTRSAIILHLSNGSVQINFFQDHTK LILCPLMAAVTYIDEKRDFRTYRLSLLEEYGCCKELASRLRYARTMVDKLLSSRSASNRL KAS Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | AlphaFold | ||||
| HIT2.0 ID | T04A2Q | |||||
| Drugs and Modes of Action | Top | |||||
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| Clinical Trial Drug(s) | [+] 8 Clinical Trial Drugs | + | ||||
| 1 | Rigosertib | Drug Info | Phase 3 | Solid tumour/cancer | [2], [3] | |
| 2 | Volasertib | Drug Info | Phase 3 | Acute myeloid leukaemia | [4] | |
| 3 | BI 2536 | Drug Info | Phase 2 | Acute myeloid leukaemia | [5], [6] | |
| 4 | PCM-075 | Drug Info | Phase 2 | Acute myeloid leukaemia | [7] | |
| 5 | CYC140 | Drug Info | Phase 1 | Acute myeloid leukaemia | [8] | |
| 6 | GSK461364 | Drug Info | Phase 1 | Non-hodgkin lymphoma | [9], [10] | |
| 7 | MK-1496 | Drug Info | Phase 1 | Solid tumour/cancer | [11] | |
| 8 | TAK-960 | Drug Info | Phase 1 | Solid tumour/cancer | [12] | |
| Discontinued Drug(s) | [+] 1 Discontinued Drugs | + | ||||
| 1 | HMN-214 | Drug Info | Discontinued in Phase 1 | Prostate cancer | [13] | |
| Preclinical Drug(s) | [+] 3 Preclinical Drugs | + | ||||
| 1 | CYC-800 | Drug Info | Preclinical | Solid tumour/cancer | [14] | |
| 2 | DAP-81 | Drug Info | Preclinical | Solid tumour/cancer | [15] | |
| 3 | ZK-thiazolidinone | Drug Info | Preclinical | Solid tumour/cancer | [16] | |
| Mode of Action | [+] 2 Modes of Action | + | ||||
| Modulator | [+] 3 Modulator drugs | + | ||||
| 1 | Rigosertib | Drug Info | [3], [17] | |||
| 2 | Volasertib | Drug Info | [1] | |||
| 3 | TAK-960 | Drug Info | [21] | |||
| Inhibitor | [+] 19 Inhibitor drugs | + | ||||
| 1 | BI 2536 | Drug Info | [15], [18] | |||
| 2 | PCM-075 | Drug Info | [7] | |||
| 3 | CYC140 | Drug Info | [19] | |||
| 4 | GSK461364 | Drug Info | [15] | |||
| 5 | MK-1496 | Drug Info | [20] | |||
| 6 | Dihydropyrido pyrazinone compound 2 | Drug Info | [22] | |||
| 7 | Dihydropyrido pyrazinone compound 3 | Drug Info | [22] | |||
| 8 | HMN-214 | Drug Info | [15], [23] | |||
| 9 | CYC-800 | Drug Info | [15] | |||
| 10 | DAP-81 | Drug Info | [15] | |||
| 11 | ZK-thiazolidinone | Drug Info | [15], [24] | |||
| 12 | CHR-4125 | Drug Info | [1] | |||
| 13 | GSK579289A | Drug Info | [25] | |||
| 14 | GW853606 | Drug Info | [26] | |||
| 15 | LC-445 | Drug Info | [15] | |||
| 16 | MLN-0905 | Drug Info | [1] | |||
| 17 | NMS-1 | Drug Info | [15] | |||
| 18 | PMID19097784C2 | Drug Info | [26] | |||
| 19 | Ro5203280 | Drug Info | [27] | |||
| Cell-based Target Expression Variations | Top | |||||
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| Cell-based Target Expression Variations | ||||||
| Drug Binding Sites of Target | Top | |||||
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| Ligand Name: Volasertib | Ligand Info | |||||
| Structure Description | PLK1 in complex with BI6727 | PDB:3FC2 | ||||
| Method | X-ray diffraction | Resolution | 2.45 Å | Mutation | Yes | [28] |
| PDB Sequence |
AKEIPEVLVD
46 PRSRRRYVRG56 RFLGKGGFAK66 CFEISDADTK76 EVFAGKIVPK86 SLLLKPHQRE 96 KMSMEISIHR106 SLAHQHVVGF116 HGFFEDNDFV126 FVVLELCRRR136 SLLELHKRRK 146 ALTEPEARYY156 LRQIVLGCQY166 LHRNRVIHRD176 LKLGNLFLNE186 DLEVKIGDFG 196 LATKVEYDGE206 RKKVLCGTPN216 YIAPEVLSKK226 GHSFEVDVWS236 IGCIMYTLLV 246 GKPPFETSCL256 KETYLRIKKN266 EYSIPKHINP276 VAASLIQKML286 QTDPTARPTI 296 NELLNDEFFT306 SGYIPARLPI316 TCLTIPPRFS326 IAP
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| Ligand Name: Tilarginine | Ligand Info | |||||
| Structure Description | Crystal structure of Polo-like kinase 1 in complex with a pyrazoloquinazoline inhibitor | PDB:3KB7 | ||||
| Method | X-ray diffraction | Resolution | 2.50 Å | Mutation | No | [29] |
| PDB Sequence |
EIPEVLVDPR
48 SRRRYVRGRF58 LGKGGFAKCF68 EISDADTKEV78 FAGKIVPKSL88 LLKPHQREKM 98 SMEISIHRSL108 AHQHVVGFHG118 FFEDNDFVFV128 VLELCRRRSL138 LELHKRRKAL 148 TEPEARYYLR158 QIVLGCQYLH168 RNRVIHRDLK178 LGNLFLNEDL188 EVKIGDFGLA 198 TKVEYDGERK208 KTLCGTPNYI218 APEVLSKKGH228 SFEVDVWSIG238 CIMYTLLVGK 248 PPFETSCLKE258 TYLRIKKNEY268 SIPKHINPVA278 ASLIQKMLQT288 DPTARPTINE 298 LLNDEFFTSG308 YIPARLPITC318 LTIPPFSIA
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| Click to View More Binding Site Information of This Target with Different Ligands | ||||||
| Different Human System Profiles of Target | Top |
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Human Similarity Proteins
of target is determined by comparing the sequence similarity of all human proteins with the target based on BLAST. The similarity proteins for a target are defined as the proteins with E-value < 0.005 and outside the protein families of the target.
A target that has fewer human similarity proteins outside its family is commonly regarded to possess a greater capacity to avoid undesired interactions and thus increase the possibility of finding successful drugs
(Brief Bioinform, 21: 649-662, 2020).
Human Pathway Affiliation
of target is determined by the life-essential pathways provided on KEGG database. The target-affiliated pathways were defined based on the following two criteria (a) the pathways of the studied target should be life-essential for both healthy individuals and patients, and (b) the studied target should occupy an upstream position in the pathways and therefore had the ability to regulate biological function.
Targets involved in a fewer pathways have greater likelihood to be successfully developed, while those associated with more human pathways increase the chance of undesirable interferences with other human processes
(Pharmacol Rev, 58: 259-279, 2006).
Biological Network Descriptors
of target is determined based on a human protein-protein interactions (PPI) network consisting of 9,309 proteins and 52,713 PPIs, which were with a high confidence score of ≥ 0.95 collected from STRING database.
The network properties of targets based on protein-protein interactions (PPIs) have been widely adopted for the assessment of target’s druggability. Proteins with high node degree tend to have a high impact on network function through multiple interactions, while proteins with high betweenness centrality are regarded to be central for communication in interaction networks and regulate the flow of signaling information
(Front Pharmacol, 9, 1245, 2018;
Curr Opin Struct Biol. 44:134-142, 2017).
Human Similarity Proteins
Human Pathway Affiliation
Biological Network Descriptors
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| KEGG Pathway | Pathway ID | Affiliated Target | Pathway Map |
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| FoxO signaling pathway | hsa04068 | Affiliated Target |
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| Class: Environmental Information Processing => Signal transduction | Pathway Hierarchy | ||
| Cell cycle | hsa04110 | Affiliated Target |
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| Class: Cellular Processes => Cell growth and death | Pathway Hierarchy | ||
| Oocyte meiosis | hsa04114 | Affiliated Target |
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| Class: Cellular Processes => Cell growth and death | Pathway Hierarchy | ||
| Progesterone-mediated oocyte maturation | hsa04914 | Affiliated Target |
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| Class: Organismal Systems => Endocrine system | Pathway Hierarchy | ||
| Degree | 74 | Degree centrality | 7.95E-03 | Betweenness centrality | 6.37E-03 |
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| Closeness centrality | 2.47E-01 | Radiality | 1.43E+01 | Clustering coefficient | 2.01E-01 |
| Neighborhood connectivity | 3.36E+01 | Topological coefficient | 4.42E-02 | Eccentricity | 12 |
| Download | Click to Download the Full PPI Network of This Target | ||||
| Chemical Structure based Activity Landscape of Target | Top |
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| Drug Property Profile of Target | Top | |
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| (1) Molecular Weight (mw) based Drug Clustering | (2) Octanol/Water Partition Coefficient (xlogp) based Drug Clustering | |
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| (3) Hydrogen Bond Donor Count (hbonddonor) based Drug Clustering | (4) Hydrogen Bond Acceptor Count (hbondacc) based Drug Clustering | |
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| (5) Rotatable Bond Count (rotbonds) based Drug Clustering | (6) Topological Polar Surface Area (polararea) based Drug Clustering | |
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| "RO5" indicates the cutoff set by lipinski's rule of five; "D123AB" colored in GREEN denotes the no violation of any cutoff in lipinski's rule of five; "D123AB" colored in PURPLE refers to the violation of only one cutoff in lipinski's rule of five; "D123AB" colored in BLACK represents the violation of more than one cutoffs in lipinski's rule of five | ||
| Co-Targets | Top | |||||
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| Co-Targets | ||||||
| Target Poor or Non Binders | Top | |||||
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| Target Poor or Non Binders | ||||||
| Target Regulators | Top | |||||
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| Target-regulating microRNAs | ||||||
| Target-interacting Proteins | ||||||
| Target Profiles in Patients | Top | |||||
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| Target Expression Profile (TEP) | ||||||
| Target-Related Models and Studies | Top | |||||
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| Target Validation | ||||||
| References | Top | |||||
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| REF 1 | URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Target id: 2168). | |||||
| REF 2 | URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 7833). | |||||
| REF 3 | Phase I study of oral rigosertib (ON 01910.Na), a dual inhibitor of the PI3K and Plk1 pathways, in adult patients with advanced solid malignancies. Clin Cancer Res. 2014 Mar 15;20(6):1656-65. | |||||
| REF 4 | Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA) | |||||
| REF 5 | URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 5666). | |||||
| REF 6 | ClinicalTrials.gov (NCT00701766) BI 2536 Infusional Treatment in Patients Over 60 Years of Age With Refractory or Relapsed Acute Myeloid Leukaemia. U.S. National Institutes of Health. | |||||
| REF 7 | Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA) | |||||
| REF 8 | ClinicalTrials.gov (NCT03884829) A Phase I Study of CYC140, a PLK-1 Inhibitor, in Advanced Leukemias or MDS. U.S. National Institutes of Health. | |||||
| REF 9 | URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 5684). | |||||
| REF 10 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800026258) | |||||
| REF 11 | ClinicalTrials.gov (NCT00880568) Phase I Study of MK-1496 in Patients With Advanced Solid Tumor (MK-1496-002 AM 4)(COMPLETED). U.S. National Institutes of Health. | |||||
| REF 12 | ClinicalTrials.gov (NCT01179399) Study of Orally Administered TAK-960 in Patients With Advanced Nonhematologic Malignancies. U.S. National Institutes of Health. | |||||
| REF 13 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800010558) | |||||
| REF 14 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800019949) | |||||
| REF 15 | Polo-like kinase (PLK) inhibitors in preclinical and early clinical development in oncology. Oncologist. 2009 Jun;14(6):559-70. | |||||
| REF 16 | Use of the Novel Plk1 Inhibitor ZK-Thiazolidinone to Elucidate Functions of Plk1 in Early and Late Stages of Mitosis. Mol Biol Cell. 2007 October; 18(10): 4024-4036. | |||||
| REF 17 | Phase I study of Rigosertib, an inhibitor of the phosphatidylinositol 3-kinase and Polo-like kinase 1 pathways, combined with gemcitabine in patients with solid tumors and pancreatic cancer.Clin Cancer Res.2012 Apr 1;18(7):2048-55. | |||||
| REF 18 | BI 2536, a potent and selective inhibitor of polo-like kinase 1, inhibits tumor growth in vivo. Curr Biol. 2007 Feb 20;17(4):316-22. | |||||
| REF 19 | Clinical pipeline report, company report or official report of Cyclacel Pharmaceuticals. | |||||
| REF 20 | J Clin Oncol 29: 2011 (suppl; abstr 3012). | |||||
| REF 21 | TAK-960, a novel, orally available, selective inhibitor of polo-like kinase 1, shows broad-spectrum preclinical antitumor activity in multiple dosing regimens. Mol Cancer Ther. 2012 Mar;11(3):700-9. | |||||
| REF 22 | BET inhibitors in cancer therapeutics: a patent review.Expert Opin Ther Pat. 2016;26(4):505-22. | |||||
| REF 23 | A phase I pharmacokinetic study of HMN-214, a novel oral stilbene derivative with polo-like kinase-1-interacting properties, in patients with advanced solid tumors. Clin Cancer Res. 2006 Sep 1;12(17):5182-9. | |||||
| REF 24 | Use of the novel Plk1 inhibitor ZK-thiazolidinone to elucidate functions of Plk1 in early and late stages of mitosis. Mol Biol Cell. 2007 Oct;18(10):4024-36. | |||||
| REF 25 | Design of potent thiophene inhibitors of polo-like kinase 1 with improved solubility and reduced protein binding. Bioorg Med Chem Lett. 2009 Mar 15;19(6):1694-7. | |||||
| REF 26 | Discovery of thiophene inhibitors of polo-like kinase. Bioorg Med Chem Lett. 2009 Feb 1;19(3):1018-21. | |||||
| REF 27 | Polo-like kinase inhibitor Ro5203280 has potent antitumor activity in nasopharyngeal carcinoma.Mol Cancer Ther. 2013 Aug;12(8):1393-401. | |||||
| REF 28 | BI 6727, a Polo-like kinase inhibitor with improved pharmacokinetic profile and broad antitumor activity. Clin Cancer Res. 2009 May 1;15(9):3094-102. | |||||
| REF 29 | Identification of 4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline derivatives as a new class of orally and selective Polo-like kinase 1 inhibitors. J Med Chem. 2010 May 13;53(9):3532-51. | |||||
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