Target General Infomation
Target ID
T49898
Former ID
TTDC00166
Target Name
Cell division control protein 2 homolog
Gene Name
CDK1
Synonyms
Cyclin-dependent kinase 1; P34 protein kinase; CDK1
Target Type
Clinical Trial
Disease Advanced solid tumor [ICD9: 140-199; ICD10: C00-C75, C7A, C7B]
Acute lymphoblastic leukemia [ICD9: 204.0, 556; ICD10: C91.0]
Breast cancer [ICD9: 174, 175; ICD10: C50]
Cancer [ICD9: 140-229; ICD10: C00-C96]
Hematological malignancies [ICD9: 200-209; ICD10: C81-C86]
Mantle cell lymphoma [ICD9: 200.4, 202.8, 203.0, 208.9; ICD10: C81-C86, C85.7, C90.0, C91-C95]
Pain [ICD9: 338, 356.0, 356.8,780; ICD10: G64, G90.0, R52, G89]
Solid tumours [ICD9: 140-199, 210-229; ICD10: C00-D48]
Small-cell lung cancer [ICD9: 162.9; ICD10: C33-C34]
Function
Plays a key role in the control of the eukaryotic cell cycle by modulating the centrosome cycle as well as mitotic onset; promotes G2-M transition, and regulates G1 progress and G1-S transition via association with multiple interphase cyclins. Required in higher cells for entry into S-phase and mitosis. Phosphorylates PARVA/actopaxin, APC, AMPH, APC, BARD1, Bcl- xL/BCL2L1, BRCA2, CALD1, CASP8, CDC7, CDC20, CDC25A, CDC25C, CC2D1A, CSNK2 proteins/CKII, FZR1/CDH1, CDK7, CEBPB, CHAMP1, DMD/dystrophin, EEF1 proteins/EF-1, EZH2, KIF11/EG5, EGFR, FANCG, FOS, GFAP, GOLGA2/GM130, GRASP1, UBE2A/hHR6A, HIST1H1 proteins/histone H1, HMGA1, HIVEP3/KRC, LMNA, LMNB, LMNC, LBR, LATS1, MAP1B, MAP4, MARCKS, MCM2, MCM4, MKLP1, MYB, NEFH, NFIC, NPC/nuclear pore complex, PITPNM1/NIR2, NPM1, NCL, NUCKS1, NPM1/numatrin, ORC1, PRKAR2A, EEF1E1/p18, EIF3F/p47, p53/TP53, NONO/p54NRB, PAPOLA, PLEC/plectin, RB1, UL40/R2, RAB4A, RAP1GAP, RCC1, RPS6KB1/S6K1, KHDRBS1/SAM68, ESPL1, SKI, BIRC5/survivin, STIP1, TEX14, beta-tubulins, MAPT/TAU, NEDD1, VIM/vimentin, TK1, FOXO1, RUNX1/AML1, SIRT2 and RUNX2. CDK1/CDC2-cyclin-B controls pronuclear union in interphase fertilized eggs. Essential for early stages of embryonic development. During G2 and early mitosis, CDC25A/B/C-mediated dephosphorylation activates CDK1/cyclin complexes which phosphorylate several substrates that trigger at least centrosome separation, Golgi dynamics, nuclear envelope breakdown and chromosome condensation. Once chromosomes are condensed and aligned at the metaphase plate, CDK1 activity is switched off by WEE1- and PKMYT1-mediated phosphorylation to allow sister chromatid separation, chromosome decondensation, reformation of the nuclear envelope and cytokinesis. Inactivated by PKR/EIF2AK2- and WEE1-mediated phosphorylation uponDNA damage to stop cell cycle and genome replication at the G2 checkpoint thus facilitating DNA repair. Reactivated after successful DNA repair through WIP1-dependent signaling leading to CDC25A/B/C-mediated dephosphorylation and restoring cell cycle progression. In proliferating cells, CDK1-mediated FOXO1 phosphorylation at the G2-M phase represses FOXO1 interaction with 14-3-3 proteins and thereby promotes FOXO1 nuclear accumulation and transcription factor activity, leading to cell death of postmitotic neurons. The phosphorylation of beta-tubulins regulates microtubule dynamics during mitosis. NEDD1 phosphorylation promotes PLK1-mediated NEDD1 phosphorylation and subsequent targeting of the gamma-tubulin ring complex (gTuRC) to the centrosome, an important step for spindle formation. In addition, CC2D1A phosphorylation regulates CC2D1A spindle pole localization and association with SCC1/RAD21 and centriole cohesion during mitosis. The phosphorylation of Bcl- xL/BCL2L1 after prolongated G2 arrest upon DNA damage triggers apoptosis. In contrast, CASP8 phosphorylation during mitosis prevents its activation by proteolysis and subsequent apoptosis. This phosphorylation occurs in cancer cell lines, as well as in primary breast tissues and lymphocytes. EZH2 phosphorylation promotes H3K27me3 maintenance and epigenetic gene silencing. CALD1 phosphorylation promotes Schwann cell migration during peripheral nerve regeneration.
BioChemical Class
Kinase
Target Validation
T49898
UniProt ID
EC Number
EC 2.7.11.23
Sequence
MEDYTKIEKIGEGTYGVVYKGRHKTTGQVVAMKKIRLESEEEGVPSTAIREISLLKELRH
PNIVSLQDVLMQDSRLYLIFEFLSMDLKKYLDSIPPGQYMDSSLVKSYLYQILQGIVFCH
SRRVLHRDLKPQNLLIDDKGTIKLADFGLARAFGIPIRVYTHEVVTLWYRSPEVLLGSAR
YSTPVDIWSIGTIFAELATKKPLFHGDSEIDQLFRIFRALGTPNNEVWPEVESLQDYKNT
FPKWKPGSLASHVKNLDENGLDLLSKMLIYDPAKRISGKMALNHPYFNDLDNQIKKM
Drugs and Mode of Action
Drug(s) P-276 Drug Info Phase 2 Breast cancer [528734], [542849]
P276-00 Drug Info Phase 2 Mantle cell lymphoma [533193]
R-roscovitine Drug Info Phase 2 Cancer [524796]
Ro 31-7453 Drug Info Phase 2 Solid tumours [531583]
AG-024322 Drug Info Phase 1 Cancer [537564]
PHA-793887 Drug Info Phase 1 Cancer [531377]
RGB-286638 Drug Info Phase 1 Hematological malignancies [523121], [542709]
ON-01135 Drug Info Preclinical Cancer [547988]
SCH 727965 Drug Info Discontinued in Phase 3 Acute lymphoblastic leukemia [531565], [533028], [542400]
BAY 10-00394 Drug Info Discontinued in Phase 2 Small-cell lung cancer [531973], [542800]
R547 Drug Info Discontinued in Phase 1 Advanced solid tumor [541047], [547737]
ZK 304709 Drug Info Discontinued in Phase 1 Advanced solid tumor [548143]
CGP-60474 Drug Info Terminated Cancer [546742]
Olomoucine Drug Info Terminated Discovery agent [546498]
Inhibitor (2,6-Diamino-pyridin-3-yl)-phenyl-methanone Drug Info [527518]
2-(p-toluidino)-4-phenylpyrimidine-5-carbonitrile Drug Info [528821]
3,4-bis(indol-3-yl)maleimide derivative Drug Info [534788]
3,4-di-(4-methoxyphenyl)-1H-pyrrole-2,5-dione Drug Info [528032]
3,4-diphenyl-1H-pyrrole-2,5-dione Drug Info [528032]
3-(4-methoxyphenyl)-4-phenyl-1H-pyrrole-2,5-dione Drug Info [528032]
3-(indole-3-yl)-4-phenyl-1H-pyrrole-2,5-dione Drug Info [528032]
4-(Quinolin-3-yl)-N-p-tolylpyrimidin-2-amine Drug Info [530491]
4-(Quinolin-4-yl)-N-p-tolylpyrimidin-2-amine Drug Info [530491]
4-phenyl-2-(phenylamino)pyrimidine-5-carbonitrile Drug Info [528821]
AG-024322 Drug Info [537564]
aloisine A Drug Info [526504]
Alsterpaullone Drug Info [535917]
alsterpaullone 2-cyanoethyl Drug Info [529213]
aminopurvalanol A Drug Info [529213]
AZAKENPAULLONE Drug Info [526916]
BAY 10-00394 Drug Info [550520]
BMS-265246 Drug Info [531328]
Cdk1 inhibitor Drug Info [529213]
Cdk1/2 inhibitor III Drug Info [527600]
CGP-60474 Drug Info [527478]
CGP74514A Drug Info [534836]
CHIR-99021 Drug Info [526553]
compound 52 Drug Info [534671]
compound 89S Drug Info [529892]
compound 9b Drug Info [529792]
CVT-313 Drug Info [529213]
GF-109203 Drug Info [534788]
Indirubin-5-Sulphonate Drug Info [551393]
JNJ-7706621 Drug Info [528188]
K00024 Drug Info [526625]
KENPAULLONE Drug Info [531040]
Microxine Drug Info [535167]
NU6140 Drug Info [527749]
ON-01135 Drug Info [544319]
P-276 Drug Info [528734]
P276-00 Drug Info [537564]
PF-228 Drug Info [528764]
PHA-793887 Drug Info [531377]
Purvalanol A Drug Info [535917]
Quinoxaline1 Drug Info [529213]
R-roscovitine Drug Info [537564]
R547 Drug Info [537564]
RGB-286638 Drug Info [532412]
Ro 31-7453 Drug Info [536474]
RO-316233 Drug Info [534788]
SCH 727965 Drug Info [537564]
Thieno analogue of kenpaullone Drug Info [526916]
ZK 304709 Drug Info [537564]
Binder 10Z-Hymenialdisine Drug Info [536555]
IN1535 Drug Info [535751]
Indirubin-3'-monoxime Drug Info [536128]
Indirubin-5-sulfonate Drug Info [535967]
Olomoucine Drug Info [536113]
Purvalanol B Drug Info [535917]
SU9516 Drug Info [535850]
Target Expression Profile (TEP) and Drug Resistance Mutation (DRM)
TEP EXP Info
Pathways
KEGG Pathway Cell cycle
Oocyte meiosis
p53 signaling pathway
Gap junction
Progesterone-mediated oocyte maturation
Herpes simplex infection
Epstein-Barr virus infection
Viral carcinogenesis
NetPath Pathway RANKL Signaling Pathway
Pathway Interaction Database p73 transcription factor network
E2F transcription factor network
PLK1 signaling events
AP-1 transcription factor network
FOXM1 transcription factor network
Retinoic acid receptors-mediated signaling
Reactome MAPK3 (ERK1) activation
E2F mediated regulation of DNA replication
G0 and Early G1
Cyclin B2 mediated events
Golgi Cisternae Pericentriolar Stack Reorganization
Phospho-APC/C mediated degradation of Cyclin A
Regulation of APC/C activators between G1/S and early anaphase
Phosphorylation of the APC/C
Phosphorylation of Emi1
Condensation of Prophase Chromosomes
MASTL Facilitates Mitotic Progression
Resolution of Sister Chromatid Cohesion
Condensation of Prometaphase Chromosomes
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
Recruitment of NuMA to mitotic centrosomes
Depolymerisation of the Nuclear Lamina
Anchoring of the basal body to the plasma membrane
MAPK6/MAPK4 signaling
G1/S-Specific Transcription
Cyclin A/B1 associated events during G2/M transition
G2/M DNA replication checkpoint
Cdk1 complex
WikiPathways DNA Damage Response
G1 to S cell cycle control
TGF beta Signaling Pathway
PPAR Alpha Pathway
MAP kinase activation in TLR cascade
RAF/MAP kinase cascade
Mitotic Prophase
Mitotic Prometaphase
BMI1
ATM Signaling Pathway
Retinoblastoma (RB) in Cancer
Spinal Cord Injury
Prostate Cancer
Regulation of Microtubule Cytoskeleton
Integrated Cancer pathway
Mitotic G2-G2/M phases
Mitotic G1-G1/S phases
Cell Cycle
APC/C-mediated degradation of cell cycle proteins
Cell Cycle Checkpoints
miRNA Regulation of DNA Damage Response
References
Ref 523121ClinicalTrials.gov (NCT01168882) Safety and Tolerability of RGB-286638 in Patients With Selected, Relapsed or Refractory Hematological Malignancies. U.S. National Institutes of Health.
Ref 524796ClinicalTrials.gov (NCT02160730) Treatment of Cushing's Disease With R-roscovitine. U.S. National Institutes of Health.
Ref 528734P276-00, a novel cyclin-dependent inhibitor induces G1-G2 arrest, shows antitumor activity on cisplatin-resistant cells and significant in vivo efficacy in tumor models. Mol Cancer Ther. 2007 Mar;6(3):926-34.
Ref 531377A first in man, phase I dose-escalation study of PHA-793887, an inhibitor of multiple cyclin-dependent kinases (CDK2, 1 and 4) reveals unexpected hepatotoxicity in patients with solid tumors. Cell Cycle. 2011 Mar 15;10(6):963-70. Epub 2011 Mar 15.
Ref 531565Cyclin-dependent kinase inhibitor Dinaciclib (SCH727965) inhibits pancreatic cancer growth and progression in murine xenograft models. Cancer Biol Ther. 2011 Oct 1;12(7):598-609. Epub 2011 Oct 1.
Ref 531583A phase 2 study of oral MKC-1, an inhibitor of importin-beta, tubulin, and the mTOR pathway in patients with unresectable or metastatic pancreatic cancer. Invest New Drugs. 2012 Aug;30(4):1614-20.
Ref 531973BAY 1000394, a novel cyclin-dependent kinase inhibitor, with potent antitumor activity in mono- and in combination treatment upon oral application. Mol Cancer Ther. 2012 Oct;11(10):2265-73.
Ref 533028Dinaciclib, a novel CDK inhibitor, demonstrates encouraging single-agent activity in patients with relapsed multiple myeloma. Blood. 2015 Jan 15;125(3):443-8.
Ref 533193A phase II, single-arm, open-label, multicenter study to evaluate the efficacy and safety of P276-00, a cyclin-dependent kinase inhibitor, in patients with relapsed or refractory mantle cell lymphoma. Clin Lymphoma Myeloma Leuk. 2015 Jul;15(7):392-7.
Ref 537564Cell cycle kinases as therapeutic targets for cancer. Nat Rev Drug Discov. 2009 Jul;8(7):547-66.
Ref 541047(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: 5707).
Ref 542400(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: 7379).
Ref 542709(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: 7744).
Ref 542800(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: 7874).
Ref 542849(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: 7934).
Ref 546498Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800008577)
Ref 546742Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800010054)
Ref 547737Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800018924)
Ref 547988Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800020976)
Ref 548143Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800022386)
Ref 526504J Med Chem. 2003 Jan 16;46(2):222-36.Aloisines, a new family of CDK/GSK-3 inhibitors. SAR study, crystal structure in complex with CDK2, enzyme selectivity, and cellular effects.
Ref 526553Selective glycogen synthase kinase 3 inhibitors potentiate insulin activation of glucose transport and utilization in vitro and in vivo. Diabetes. 2003 Mar;52(3):588-95.
Ref 526625Synthesis, structure-activity relationship, and biological studies of indolocarbazoles as potent cyclin D1-CDK4 inhibitors. J Med Chem. 2003 May 22;46(11):2027-30.
Ref 526916Bioorg Med Chem Lett. 2004 Jan 19;14(2):413-6.1-Azakenpaullone is a selective inhibitor of glycogen synthase kinase-3 beta.
Ref 527478J Med Chem. 2005 Mar 24;48(6):1886-900.Synthesis and discovery of pyrazine-pyridine biheteroaryl as a novel series of potent vascular endothelial growth factor receptor-2 inhibitors.
Ref 527518Bioorg Med Chem Lett. 2005 May 2;15(9):2221-4.3-Acyl-2,6-diaminopyridines as cyclin-dependent kinase inhibitors: synthesis and biological evaluation.
Ref 5276001-Acyl-1H-[1,2,4]triazole-3,5-diamine analogues as novel and potent anticancer cyclin-dependent kinase inhibitors: synthesis and evaluation of biological activities. J Med Chem. 2005 Jun 30;48(13):4208-11.
Ref 527749Potentiation of paclitaxel-induced apoptosis by the novel cyclin-dependent kinase inhibitor NU6140: a possible role for survivin down-regulation. Mol Cancer Ther. 2005 Sep;4(9):1328-37.
Ref 528032J Med Chem. 2006 Feb 23;49(4):1271-81.Design, synthesis, and biological evaluation of 3,4-diarylmaleimides as angiogenesis inhibitors.
Ref 528188Bioorg Med Chem Lett. 2006 Jul 15;16(14):3639-41. Epub 2006 May 6.Synthesis and evaluation of N-acyl sulfonamides as potential prodrugs of cyclin-dependent kinase inhibitor JNJ-7706621.
Ref 528734P276-00, a novel cyclin-dependent inhibitor induces G1-G2 arrest, shows antitumor activity on cisplatin-resistant cells and significant in vivo efficacy in tumor models. Mol Cancer Ther. 2007 Mar;6(3):926-34.
Ref 528764J Biol Chem. 2007 May 18;282(20):14845-52. Epub 2007 Mar 28.Cellular characterization of a novel focal adhesion kinase inhibitor.
Ref 528821Bioorg Med Chem Lett. 2007 Jun 15;17(12):3266-70. Epub 2007 Apr 10.4-Aryl-5-cyano-2-aminopyrimidines as VEGF-R2 inhibitors: synthesis and biological evaluation.
Ref 529213Proc Natl Acad Sci U S A. 2007 Dec 18;104(51):20523-8. Epub 2007 Dec 11.A systematic interaction map of validated kinase inhibitors with Ser/Thr kinases.
Ref 529792Bioorg Med Chem Lett. 2008 Dec 15;18(24):6486-9. Epub 2008 Oct 22.Imidazole pyrimidine amides as potent, orally bioavailable cyclin-dependent kinase inhibitors.
Ref 529892First Cdc7 kinase inhibitors: pyrrolopyridinones as potent and orally active antitumor agents. 2. Lead discovery. J Med Chem. 2009 Jan 22;52(2):293-307.
Ref 530491Eur J Med Chem. 2010 Jan;45(1):379-86. Epub 2009 Oct 13.Synthesis and cytotoxic activity of 2-methylimidazo[1,2-a]pyridine- and quinoline-substituted 2-aminopyrimidine derivatives.
Ref 531040Eur J Med Chem. 2010 Sep;45(9):4316-30. Epub 2010 Jun 30.Discovery of novel CDK1 inhibitors by combining pharmacophore modeling, QSAR analysis and in silico screening followed by in vitro bioassay.
Ref 531328A robust high-content imaging approach for probing the mechanism of action and phenotypic outcomes of cell-cycle modulators. Mol Cancer Ther. 2011 Feb;10(2):242-54.
Ref 531377A first in man, phase I dose-escalation study of PHA-793887, an inhibitor of multiple cyclin-dependent kinases (CDK2, 1 and 4) reveals unexpected hepatotoxicity in patients with solid tumors. Cell Cycle. 2011 Mar 15;10(6):963-70. Epub 2011 Mar 15.
Ref 532412Small-molecule multi-targeted kinase inhibitor RGB-286638 triggers P53-dependent and -independent anti-multiple myeloma activity through inhibition of transcriptional CDKs. Leukemia. 2013 Dec;27(12):2366-75.
Ref 534671Exploiting chemical libraries, structure, and genomics in the search for kinase inhibitors. Science. 1998 Jul 24;281(5376):533-8.
Ref 534788Bioorg Med Chem Lett. 1998 May 5;8(9):1019-22.Design of new inhibitors for cdc2 kinase based on a multiple pseudosubstrate structure.
Ref 5348362,6,9-trisubstituted purines: optimization towards highly potent and selective CDK1 inhibitors. Bioorg Med Chem Lett. 1999 Jan 4;9(1):91-6.
Ref 535167Microxine, a new cdc2 kinase inhibitor from the Australian marine sponge Microxina species. J Nat Prod. 2001 Apr;64(4):525-6.
Ref 535751M-phase regulation of the recruitment of mRNAs onto polysomes using the CDK1/cyclin B inhibitor aminopurvalanol. Biochem Biophys Res Commun. 2003 Jul 11;306(4):880-6.
Ref 535850SU9516: biochemical analysis of cdk inhibition and crystal structure in complex with cdk2. Biochem Biophys Res Commun. 2003 Oct 24;310(3):1026-31.
Ref 535917Down-regulation of survivin in nitric oxide-induced cell growth inhibition and apoptosis of the human lung carcinoma cells. J Biol Chem. 2004 May 7;279(19):20267-76. Epub 2004 Feb 26.
Ref 535967Binding of the potential antitumour agent indirubin-5-sulphonate at the inhibitor site of rabbit muscle glycogen phosphorylase b. Comparison with ligand binding to pCDK2-cyclin A complex. Eur J Biochem. 2004 Jun;271(11):2280-90.
Ref 536113Antiproliferative activity of olomoucine II, a novel 2,6,9-trisubstituted purine cyclin-dependent kinase inhibitor. Cell Mol Life Sci. 2005 Aug;62(15):1763-71.
Ref 536128The kinase inhibitor indirubin-3'-oxime prevents germinal vesicle breakdown and reduces parthenogenetic development of pig oocytes. Theriogenology. 2006 Mar 1;65(4):744-56. Epub 2005 Aug 18.
Ref 536474A comparison of physicochemical property profiles of marketed oral drugs and orally bioavailable anti-cancer protein kinase inhibitors in clinical development. Curr Top Med Chem. 2007;7(14):1408-22.
Ref 536555DrugBank: a knowledgebase for drugs, drug actions and drug targets. Nucleic Acids Res. 2008 Jan;36(Database issue):D901-6. Epub 2007 Nov 29.
Ref 537564Cell cycle kinases as therapeutic targets for cancer. Nat Rev Drug Discov. 2009 Jul;8(7):547-66.
Ref 544319Phase 1 study of intravenous rigosertib (ON 01910.Na), a novel benzyl styryl sulfone structure producing G2/M arrest and apoptosis, in adult patients with advanced cancer. Am J Cancer Res. 2013; 3(3): 323-338.
Ref 550520National Cancer Institute Drug Dictionary (drug id 770319).
Ref 551393How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6.
Ref 1587926URL: https://www.ebi.ac.uk/chembl/ The ChEMBL database in 2017

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