Target Information

Target General Infomation
Target ID
T40694
Former ID
TTDC00160
Target Name
Serine/threonine-protein kinase PLK1
Gene Name
PLK1
Synonyms
Mitoticserine-threonine kinase polo-like kinase 1; PLK-1; Plk1; Polo-like kinase 1; STPK13; Serine-threonine protein kinase 13; PLK1
Target Type
Clinical Trial
Disease Advanced solid tumor; Non-hodgkin's lymphoma [ICD9: 140-199, 200, 202, 202.8, 210-229; ICD10: C00-C75, C7A, C7B, C81-C86, C82-C85, D10-D36, D3A]
Acute myeloid leukemia [ICD9: 205; ICD10: C92.0]
Cancer [ICD9: 140-229; ICD10: C00-C96]
Lymphoma [ICD9: 202.8, 208.9; ICD10: C81-C86]
Pancreatic cancer; Prostate cancer [ICD9: 157, 185; ICD10: C25, C61]
Solid tumours [ICD9: 140-199, 210-229; ICD10: C00-D48]
Function
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 cohesinsfrom chromosome arms, the inactivation of anaphase-promoting complex/cyclosome (APC/C) inhibitors, and the regulation of mitotic exit and cytokinesis. 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, SGOL1, STAG2/SA2, TEX14, TOPORS, p73/TP73, TPT1 and WEE1. 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.
BioChemical Class
Kinase
Target Validation
T40694
UniProt ID
P53350
EC Number
EC 2.7.11.21
Sequence
MSAAVTAGKLARAPADPGKAGVPGVAAPGAPAAAPPAKEIPEVLVDPRSRRRYVRGRFLG
KGGFAKCFEISDADTKEVFAGKIVPKSLLLKPHQREKMSMEISIHRSLAHQHVVGFHGFF
EDNDFVFVVLELCRRRSLLELHKRRKALTEPEARYYLRQIVLGCQYLHRNRVIHRDLKLG
NLFLNEDLEVKIGDFGLATKVEYDGERKKTLCGTPNYIAPEVLSKKGHSFEVDVWSIGCI
MYTLLVGKPPFETSCLKETYLRIKKNEYSIPKHINPVAASLIQKMLQTDPTARPTINELL
NDEFFTSGYIPARLPITCLTIPPRFSIAPSSLDPSNRKPLTVLNKGLENPLPERPREKEE
PVVRETGEVVDCHLSDMLQQLHSVNASKPSERGLVRQEEAEDPACIPIFWVSKWVDYSDK
YGLGYQLCDNSVGVLFNDSTRLILYNDGDSLQYIERDGTESYLTVSSHPNSLMKKITLLK
YFRNYMSEHLLKAGANITPREGDELARLPYLRTWFRTRSAIILHLSNGSVQINFFQDHTK
LILCPLMAAVTYIDEKRDFRTYRLSLLEEYGCCKELASRLRYARTMVDKLLSSRSASNRL
KAS
Drugs and Mode of Action
Drug(s) Rigosertib Drug Info Phase 3 Solid tumours [532659], [542777]
BI 2536 Drug Info Phase 2 Acute myeloid leukemia [522354], [541009]
Volasertib Drug Info Phase 2 Acute myeloid leukemia [524843], [542862]
GSK461364 Drug Info Phase 1 Advanced solid tumor; Non-hodgkin's lymphoma [541028], [548516]
MK-1496 Drug Info Phase 1 Solid tumours [522634]
NMS-1286937 Drug Info Phase 1 Solid tumours [522856], [542837]
TAK-960 Drug Info Phase 1 Solid tumours [523131]
CYC-800 Drug Info Preclinical Cancer [547859]
DAP-81 Drug Info Preclinical Cancer [537386]
ON 019190.Na Drug Info Preclinical Cancer [537386]
ZK-thiazolidinone Drug Info Preclinical Cancer [544035]
HMN-214 Drug Info Discontinued in Phase 1 Pancreatic cancer; Prostate cancer [546839]
Inhibitor BI 2536 Drug Info [536354], [537386]
CHR-4125 Drug Info [543565]
compound 2 Drug Info [529878]
CYC-800 Drug Info [537386]
DAP-81 Drug Info [537386]
GSK461364 Drug Info [537386]
GSK579289A Drug Info [529981]
GW853606 Drug Info [529878]
HMN-214 Drug Info [536270], [537386]
LC-445 Drug Info [537386]
MK-1496 Drug Info [549710]
MLN-0905 Drug Info [543565]
NMS-1 Drug Info [537386]
ON 019190.Na Drug Info [537386]
ZK-thiazolidinone Drug Info [536464], [537386]
Modulator NMS-1286937 Drug Info [522856]
Rigosertib Drug Info [532659]
TAK-960 Drug Info [531743]
Volasertib Drug Info [543565]
Target Expression Profile (TEP) and Drug Resistance Mutation (DRM)
TEP EXP Info
Pathways
KEGG Pathway FoxO signaling pathway
Cell cycle
Oocyte meiosis
Progesterone-mediated oocyte maturation
Pathway Interaction Database p73 transcription factor network
ATR signaling pathway
PLK1 signaling events
FoxO family signaling
FOXM1 transcription factor network
Validated transcriptional targets of TAp63 isoforms
Polo-like kinase signaling events in the cell cycle
Reactome Polo-like kinase mediated events
Golgi Cisternae Pericentriolar Stack Reorganization
Cdh1 targeted proteins in late mitosis/early G1
Phosphorylation of the APC/C
Phosphorylation of Emi1
Condensation of Prophase Chromosomes
Separation of Sister Chromatids
Resolution of Sister Chromatid Cohesion
Regulation of PLK1 Activity at G2/M Transition
Activation of NIMA Kinases NEK9, NEK6, NEK7
Loss of Nlp from mitotic centrosomes
Recruitment of mitotic centrosome proteins and complexes
Loss of proteins required for interphase microtubule organization?from the centrosome
Anchoring of the basal body to the plasma membrane
RHO GTPases Activate Formins
Mitotic Prometaphase
Cyclin A/B1 associated events during G2/M transition
WikiPathways Mitotic Telophase/Cytokinesis
Mitotic Metaphase and Anaphase
Mitotic Prophase
Mitotic Prometaphase
Integrated Pancreatic Cancer Pathway
TNF alpha Signaling Pathway
Prostate Cancer
miR-targeted genes in muscle cell - TarBase
miR-targeted genes in lymphocytes - TarBase
miR-targeted genes in epithelium - TarBase
Integrated Breast Cancer Pathway
Integrated Cancer pathway
Mitotic G2-G2/M phases
Cell Cycle
APC/C-mediated degradation of cell cycle proteins
Regulation of toll-like receptor signaling pathway
References
Ref 522354ClinicalTrials.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 522634ClinicalTrials.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 522856ClinicalTrials.gov (NCT01014429) Study of NMS-1286937 in Adult Patients With Advanced/Metastatic Solid Tumors. U.S. National Institutes of Health.
Ref 523131ClinicalTrials.gov (NCT01179399) Study of Orally Administered TAK-960 in Patients With Advanced Nonhematologic Malignancies. U.S. National Institutes of Health.
Ref 524843ClinicalTrials.gov (NCT02198482) Trial of Intensive Chemotherapy With or Without Volasertib in Patients With Newly Diagnosed Acute Myeloid Leukemia. U.S. National Institutes of Health.
Ref 532659Phase 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 537386Polo-like kinase (PLK) inhibitors in preclinical and early clinical development in oncology. Oncologist. 2009 Jun;14(6):559-70. Epub 2009 May 27.
Ref 541009(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 541028(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 542777(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 542837(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: 7918).
Ref 542862(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: 7947).
Ref 544035Use 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 546839Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800010558)
Ref 547859Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800019949)
Ref 548516Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800026258)
Ref 522856ClinicalTrials.gov (NCT01014429) Study of NMS-1286937 in Adult Patients With Advanced/Metastatic Solid Tumors. U.S. National Institutes of Health.
Ref 529878Discovery of thiophene inhibitors of polo-like kinase. Bioorg Med Chem Lett. 2009 Feb 1;19(3):1018-21.
Ref 529981Design 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 531743TAK-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 532659Phase 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 536270A 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 536354BI 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. Epub 2007 Feb 8.
Ref 536464Use 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. Epub 2007 Aug 1.
Ref 537386Polo-like kinase (PLK) inhibitors in preclinical and early clinical development in oncology. Oncologist. 2009 Jun;14(6):559-70. Epub 2009 May 27.
Ref 543565(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 549710J Clin Oncol 29: 2011 (suppl; abstr 3012).

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