Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTIYVQP)

• DTT Name: Polo-like kinase 1 (PLK1)
• 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
• Gene Name: PLK1
• DTT Type: Clinical trial target; [1]
• BioChemical Class: Kinase
• UniProt ID: PLK1_HUMAN
• TTD ID: T40694
• EC Number: EC 2.7.11.21
• Sequence:
  MSAAVTAGKLARAPADPGKAGVPGVAAPGAPAAAPPAKEIPEVLVDPRSRRRYVRGRFLG
  KGGFAKCFEISDADTKEVFAGKIVPKSLLLKPHQREKMSMEISIHRSLAHQHVVGFHGFF
  EDNDFVFVVLELCRRRSLLELHKRRKALTEPEARYYLRQIVLGCQYLHRNRVIHRDLKLG
  NLFLNEDLEVKIGDFGLATKVEYDGERKKTLCGTPNYIAPEVLSKKGHSFEVDVWSIGCI
  MYTLLVGKPPFETSCLKETYLRIKKNEYSIPKHINPVAASLIQKMLQTDPTARPTINELL
  NDEFFTSGYIPARLPITCLTIPPRFSIAPSSLDPSNRKPLTVLNKGLENPLPERPREKEE
  PVVRETGEVVDCHLSDMLQQLHSVNASKPSERGLVRQEEAEDPACIPIFWVSKWVDYSDK
  YGLGYQLCDNSVGVLFNDSTRLILYNDGDSLQYIERDGTESYLTVSSHPNSLMKKITLLK
  YFRNYMSEHLLKAGANITPREGDELARLPYLRTWFRTRSAIILHLSNGSVQINFFQDHTK
  LILCPLMAAVTYIDEKRDFRTYRLSLLEEYGCCKELASRLRYARTMVDKLLSSRSASNRL
  KAS
• 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.
• KEGG Pathway:
  FoxO signaling pathway (hsa04068)
  Cell cycle (hsa04110)
  Oocyte meiosis (hsa04114)
  Progesterone-mediated oocyte maturation (hsa04914)
• Reactome Pathway:
  Golgi Cisternae Pericentriolar Stack Reorganization (R-HSA-162658)
  APC/C (R-HSA-174178)
  Phosphorylation of the APC/C (R-HSA-176412)
  Phosphorylation of Emi1 (R-HSA-176417)
  Condensation of Prophase Chromosomes (R-HSA-2299718)
  Separation of Sister Chromatids (R-HSA-2467813)
  Resolution of Sister Chromatid Cohesion (R-HSA-2500257)
  Regulation of PLK1 Activity at G2/M Transition (R-HSA-2565942)
  Activation of NIMA Kinases NEK9, NEK6, NEK7 (R-HSA-2980767)
  Loss of Nlp from mitotic centrosomes (R-HSA-380259)
  Recruitment of mitotic centrosome proteins and complexes (R-HSA-380270)
  Loss of proteins required for interphase microtubule organization?from the centrosome (R-HSA-380284)
  Anchoring of the basal body to the plasma membrane (R-HSA-5620912)
  RHO GTPases Activate Formins (R-HSA-5663220)
  Mitotic Prometaphase (R-HSA-68877)
  Cyclin A/B1 associated events during G2/M transition (R-HSA-69273)
  Polo-like kinase mediated events (R-HSA-156711)

Molecular Interaction Atlas (MIA) of This DTT

8 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Rigosertib	DMOSTXF	Myelodysplastic syndrome	2A37	Phase 3	[2]
Volasertib	DMOFH1M	Acute myeloid leukaemia	2A60	Phase 3	[1]
BI 2536	DMJSADP	Acute myeloid leukaemia	2A60	Phase 2	[3]
PCM-075	DMYFRTB	Acute myeloid leukaemia	2A60	Phase 2	[4]
CYC140	DMC6PKJ	Acute myeloid leukaemia	2A60	Phase 1	[5]
GSK461364	DM0P729	Non-hodgkin lymphoma	2B33.5	Phase 1	[3]
MK-1496	DME1ZAH	Solid tumour/cancer	2A00-2F9Z	Phase 1	[6]
TAK-960	DMN4OGH	Solid tumour/cancer	2A00-2F9Z	Phase 1	[7]

2 Patented Agent(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Dihydropyrido pyrazinone compound 2	DMOTG2Y	N. A.	N. A.	Patented	[8]
Dihydropyrido pyrazinone compound 3	DM3PEUN	N. A.	N. A.	Patented	[8]

1 Discontinued Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
HMN-214	DMH4ANG	Pancreatic cancer	2C10	Discontinued in Phase 1	[3]

3 Preclinical Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
CYC-800	DMA1MK5	Solid tumour/cancer	2A00-2F9Z	Preclinical	[3]
DAP-81	DMUWRIF	Solid tumour/cancer	2A00-2F9Z	Preclinical	[3]
ZK-thiazolidinone	DMNG84V	Solid tumour/cancer	2A00-2F9Z	Preclinical	[3]

8 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
CHR-4125	DMXKU73	Solid tumour/cancer	2A00-2F9Z	Investigative	[1]
GSK579289A	DMJXHU8	Discovery agent	N.A.	Investigative	[9]
GW853606	DMITKX8	Discovery agent	N.A.	Investigative	[10]
LC-445	DMYONVF	Solid tumour/cancer	2A00-2F9Z	Investigative	[3]
MLN-0905	DMTU0IG	Lymphoma	2A80-2A86	Investigative	[1]
NMS-1	DMX4ZGL	Solid tumour/cancer	2A00-2F9Z	Investigative	[3]
PMID19097784C2	DMH70UC	Discovery agent	N.A.	Investigative	[10]
Ro5203280	DM42UK5	Nasopharyngeal carcinoma	2B6B	Investigative	[11]

Molecular Expression Atlas (MEA) of This DTT

Disease Name	ICD 11	Studied Tissue	p-value	Fold-Change	Z-score
Acute myelocytic leukaemia	2C82	Bone marrow	4.16E-07	-0.38	-0.72

References

• [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).
• [2] 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.
• [3] Polo-like kinase (PLK) inhibitors in preclinical and early clinical development in oncology. Oncologist. 2009 Jun;14(6):559-70.
• [4] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [5] Clinical pipeline report, company report or official report of Cyclacel Pharmaceuticals.
• [6] J Clin Oncol 29: 2011 (suppl; abstr 3012).
• [7] 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.
• [8] BET inhibitors in cancer therapeutics: a patent review.Expert Opin Ther Pat. 2016;26(4):505-22.
• [9] 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.
• [10] Discovery of thiophene inhibitors of polo-like kinase. Bioorg Med Chem Lett. 2009 Feb 1;19(3):1018-21.
• [11] Polo-like kinase inhibitor Ro5203280 has potent antitumor activity in nasopharyngeal carcinoma.Mol Cancer Ther. 2013 Aug;12(8):1393-401.