Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTH6V3D)

• DTT Name: Cyclin-dependent kinase 1 (CDK1)
• Synonyms: P34CDC2; P34 protein kinase; CDKN1; CDC28A; CDC2
• Gene Name: CDK1
• DTT Type: Clinical trial target; [1]
• BioChemical Class: Kinase
• UniProt ID: CDK1_HUMAN
• TTD ID: T49898
• EC Number: EC 2.7.11.22
• Sequence:
  MEDYTKIEKIGEGTYGVVYKGRHKTTGQVVAMKKIRLESEEEGVPSTAIREISLLKELRH
  PNIVSLQDVLMQDSRLYLIFEFLSMDLKKYLDSIPPGQYMDSSLVKSYLYQILQGIVFCH
  SRRVLHRDLKPQNLLIDDKGTIKLADFGLARAFGIPIRVYTHEVVTLWYRSPEVLLGSAR
  YSTPVDIWSIGTIFAELATKKPLFHGDSEIDQLFRIFRALGTPNNEVWPEVESLQDYKNT
  FPKWKPGSLASHVKNLDENGLDLLSKMLIYDPAKRISGKMALNHPYFNDLDNQIKKM
• Function: 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, CENPA, 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, SAMHD1, 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 upon DNA 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. CDK1-cyclin-B complex phosphorylates NCKAP5L and mediates its dissociation from centrosomes during mitosis. Regulates the amplitude of the cyclic expression of the core clock gene ARNTL/BMAL1 by phosphorylating its transcriptional repressor NR1D1, and this phosphorylation is necessary for SCF(FBXW7)-mediated ubiquitination and proteasomal degradation of NR1D1. 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.
• KEGG Pathway:
  Cell cycle (hsa04110)
  Oocyte meiosis (hsa04114)
  p53 signaling pathway (hsa04115)
  Gap junction (hsa04540)
  Progesterone-mediated oocyte maturation (hsa04914)
  Herpes simplex infection (hsa05168)
  Epstein-Barr virus infection (hsa05169)
  Viral carcinogenesis (hsa05203)
• Reactome Pathway:
  E2F mediated regulation of DNA replication (R-HSA-113510)
  G0 and Early G1 (R-HSA-1538133)
  Cyclin B2 mediated events (R-HSA-157881)
  Golgi Cisternae Pericentriolar Stack Reorganization (R-HSA-162658)
  Cdc20 (R-HSA-174184)
  Regulation of APC/C activators between G1/S and early anaphase (R-HSA-176408)
  Phosphorylation of the APC/C (R-HSA-176412)
  Phosphorylation of Emi1 (R-HSA-176417)
  Condensation of Prophase Chromosomes (R-HSA-2299718)
  MASTL Facilitates Mitotic Progression (R-HSA-2465910)
  Resolution of Sister Chromatid Cohesion (R-HSA-2500257)
  Condensation of Prometaphase Chromosomes (R-HSA-2514853)
  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)
  Recruitment of NuMA to mitotic centrosomes (R-HSA-380320)
  Depolymerisation of the Nuclear Lamina (R-HSA-4419969)
  Anchoring of the basal body to the plasma membrane (R-HSA-5620912)
  MAPK6/MAPK4 signaling (R-HSA-5687128)
  G1/S-Specific Transcription (R-HSA-69205)
  Cyclin A/B1 associated events during G2/M transition (R-HSA-69273)
  G2/M DNA replication checkpoint (R-HSA-69478)
  Chk1/Chk2(Cds1) mediated inactivation of Cyclin B (R-HSA-75035)
  MAPK3 (ERK1) activation (R-HSA-110056)

Molecular Interaction Atlas (MIA) of This DTT

7 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
P-276	DMMJUHD	Breast cancer	2C60-2C65	Phase 2	[2]
P276-00	DM9DJL2	Mantle cell lymphoma	2A85.5	Phase 2	[1]
R-roscovitine	DMSH108	Non-small-cell lung cancer	2C25.Y	Phase 2	[1]
Ro 31-7453	DM83QCL	Solid tumour/cancer	2A00-2F9Z	Phase 2	[3]
AG-024322	DMY4WVK	Solid tumour/cancer	2A00-2F9Z	Phase 1	[1]
PHA-793887	DM2Y4FG	Solid tumour/cancer	2A00-2F9Z	Phase 1	[4]
RGB-286638	DMEGOQP	Haematological malignancy	2B33.Y	Phase 1	[5]

13 Patented Agent(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
4-(thiazol-5-yl)-pyrimidine derivative 2	DMMQFCN	N. A.	N. A.	Patented	[6]
CHIR-99021	DMB8MNU	Allergic inflammation	4A80-4A85	Patented	[7]
Indole-based analog 13	DMV7DFM	N. A.	N. A.	Patented	[6]
Isoquinoline 1,3-dione derivative 1	DMIYUAN	N. A.	N. A.	Patented	[6]
KENPAULLONE	DMAGVXW	Discovery agent	N.A.	Patented	[8]
Naphthyridine and isoquinoline derivative 1	DMTGIP7	N. A.	N. A.	Patented	[6]
Oxazolyl methylthiothiazole derivative 1	DMZM6FW	N. A.	N. A.	Patented	[6]
PMID25991433-Compound-A1	DM89LF0	N. A.	N. A.	Patented	[9]
Pyrazolo[1,5-a]-1,3,5-triazine derivative 1	DMOK7CW	N. A.	N. A.	Patented	[6]
Pyrrolo[2,3-d]pyrimidine derivative 10	DMRWG2E	N. A.	N. A.	Patented	[6]
Pyrrolo[2,3-d]pyrimidine derivative 9	DM0HU5O	N. A.	N. A.	Patented	[6]
Roscovitine derivative 1	DMD1G3Z	N. A.	N. A.	Patented	[6]
Tricyclic benzimidazole derivative 1	DM5SD9E	N. A.	N. A.	Patented	[6]

6 Discontinued Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
SCH 727965	DMCJLD1	Acute lymphoblastic leukaemia	2A85	Discontinued in Phase 3	[1]
BAY 10-00394	DMV2DIW	Small-cell lung cancer	2C25.Y	Discontinued in Phase 2	[10]
R547	DMK25FU	Advanced solid tumour	2A00-2F9Z	Discontinued in Phase 1	[1]
ZK 304709	DMJ9R4A	Advanced solid tumour	2A00-2F9Z	Discontinued in Phase 1	[1]
CGP-60474	DM4TGY0	Solid tumour/cancer	2A00-2F9Z	Terminated	[13]
Olomoucine	DMNAFG1	N. A.	N. A.	Terminated	[14]

2 Preclinical Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
L-751250	DMOERXK	Obesity	5B81	Preclinical	[11]
ON-01135	DMEXLU5	Solid tumour/cancer	2A00-2F9Z	Preclinical	[12]

37 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
(2,6-Diamino-pyridin-3-yl)-phenyl-methanone	DMWRCM1	Discovery agent	N.A.	Investigative	[15]
10Z-Hymenialdisine	DMIRSA5	Discovery agent	N.A.	Investigative	[16]
2-(p-toluidino)-4-phenylpyrimidine-5-carbonitrile	DM27YTF	Discovery agent	N.A.	Investigative	[17]
3,4-bis(indol-3-yl)maleimide derivative	DMEQ1HC	Discovery agent	N.A.	Investigative	[18]
3,4-di-(4-methoxyphenyl)-1H-pyrrole-2,5-dione	DMDO175	Discovery agent	N.A.	Investigative	[19]
3,4-diphenyl-1H-pyrrole-2,5-dione	DMPK6YT	Discovery agent	N.A.	Investigative	[19]
3-(4-methoxyphenyl)-4-phenyl-1H-pyrrole-2,5-dione	DMGC7RY	Discovery agent	N.A.	Investigative	[19]
3-(indole-3-yl)-4-phenyl-1H-pyrrole-2,5-dione	DM3EV9N	Discovery agent	N.A.	Investigative	[19]
4-(Quinolin-3-yl)-N-p-tolylpyrimidin-2-amine	DM4YFU5	Discovery agent	N.A.	Investigative	[20]
4-(Quinolin-4-yl)-N-p-tolylpyrimidin-2-amine	DMDW3SX	Discovery agent	N.A.	Investigative	[20]
4-phenyl-2-(phenylamino)pyrimidine-5-carbonitrile	DMONKDQ	Discovery agent	N.A.	Investigative	[17]
9-Nitropaullone	DM8LUYM	Discovery agent	N.A.	Investigative	[11]
aloisine A	DM5U1LN	Discovery agent	N.A.	Investigative	[21]
alsterpaullone 2-cyanoethyl	DMDI2KH	Discovery agent	N.A.	Investigative	[22]
aminopurvalanol A	DMKLC3O	N. A.	N. A.	Investigative	[22]
AZAKENPAULLONE	DM61H07	Discovery agent	N.A.	Investigative	[23]
Bisindolylmaleimide-I	DMOQJZC	Discovery agent	N.A.	Investigative	[18]
BMS-265246	DM6LPIG	Discovery agent	N.A.	Investigative	[24]
Cdk1 inhibitor	DMNW12R	Discovery agent	N.A.	Investigative	[22]
Cdk1/2 inhibitor III	DMS62T0	Discovery agent	N.A.	Investigative	[25]
CGP74514A	DMU5984	Discovery agent	N.A.	Investigative	[26]
CVT-313	DMSEK5W	Discovery agent	N.A.	Investigative	[22]
IN1535	DMKFE6X	Discovery agent	N.A.	Investigative	[27]
Indirubin-3'-monoxime	DMLRQH0	Discovery agent	N.A.	Investigative	[28]
Indirubin-5-sulfonate	DM08VHZ	Discovery agent	N.A.	Investigative	[29]
JNJ-7706621	DMHTYBS	Discovery agent	N.A.	Investigative	[30]
K00024	DMP8M9Q	Discovery agent	N.A.	Investigative	[31]
Microxine	DM7Y9AD	Pain	MG30-MG3Z	Investigative	[32]
NU6140	DMCUSG3	Discovery agent	N.A.	Investigative	[33]
PF-228	DM32FKD	Discovery agent	N.A.	Investigative	[34]
PMID18986805C9b	DMFU6AI	Discovery agent	N.A.	Investigative	[35]
PMID19115845C89S	DMB9F2L	Discovery agent	N.A.	Investigative	[36]
Purvalanol A	DMNQ7TM	Discovery agent	N.A.	Investigative	[11]
Quinoxaline1	DMRWXH4	Discovery agent	N.A.	Investigative	[22]
RO-316233	DMAGLPW	Discovery agent	N.A.	Investigative	[18]
SU9516	DMQHG0R	Discovery agent	N.A.	Investigative	[37]
Thieno analogue of kenpaullone	DMIOTHG	Discovery agent	N.A.	Investigative	[23]

Molecular Expression Atlas (MEA) of This DTT

Disease Name	ICD 11	Studied Tissue	p-value	Fold-Change	Z-score
Lung cancer	2C82	Lung tissue	5.27E-108	1.97	3.12
Breast cancer	2C82	Breast tissue	1.01E-295	2.78	5.21

References

• [1] Cell cycle kinases as therapeutic targets for cancer. Nat Rev Drug Discov. 2009 Jul;8(7):547-66.
• [2] P276-00, 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.
• [3] A 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.
• [4] A first in man, phase I dose-escalation study of PHA-793887, an inhibitor of multiple cyclin-dependent kinases (CDK2, 1 and 4) reveals unexpected h... Cell Cycle. 2011 Mar 15;10(6):963-70.
• [5] Small-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.
• [6] Cyclin-dependent kinase inhibitors for cancer therapy: a patent review (2009 - 2014).Expert Opin Ther Pat. 2015;25(9):953-70.
• [7] Selective 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.
• [8] Discovery of novel CDK1 inhibitors by combining pharmacophore modeling, QSAR analysis and in silico screening followed by in vitro bioassay. Eur J Med Chem. 2010 Sep;45(9):4316-30.
• [9] c-Jun N-terminal kinase inhibitors: a patent review (2010 - 2014).Expert Opin Ther Pat. 2015;25(8):849-72.
• [10] National Cancer Institute Drug Dictionary (drug id 770319).
• [11] Down-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.
• [12] Phase 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.
• [13] Synthesis and discovery of pyrazine-pyridine biheteroaryl as a novel series of potent vascular endothelial growth factor receptor-2 inhibitors. J Med Chem. 2005 Mar 24;48(6):1886-900.
• [14] Antiproliferative 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.
• [15] 3-Acyl-2,6-diaminopyridines as cyclin-dependent kinase inhibitors: synthesis and biological evaluation. Bioorg Med Chem Lett. 2005 May 2;15(9):2221-4.
• [16] DrugBank: a knowledgebase for drugs, drug actions and drug targets. Nucleic Acids Res. 2008 Jan;36(Database issue):D901-6.
• [17] 4-Aryl-5-cyano-2-aminopyrimidines as VEGF-R2 inhibitors: synthesis and biological evaluation. Bioorg Med Chem Lett. 2007 Jun 15;17(12):3266-70.
• [18] Design of new inhibitors for cdc2 kinase based on a multiple pseudosubstrate structure. Bioorg Med Chem Lett. 1998 May 5;8(9):1019-22.
• [19] Design, synthesis, and biological evaluation of 3,4-diarylmaleimides as angiogenesis inhibitors. J Med Chem. 2006 Feb 23;49(4):1271-81.
• [20] Synthesis and cytotoxic activity of 2-methylimidazo[1,2-a]pyridine- and quinoline-substituted 2-aminopyrimidine derivatives. Eur J Med Chem. 2010 Jan;45(1):379-86.
• [21] Aloisines, a new family of CDK/GSK-3 inhibitors. SAR study, crystal structure in complex with CDK2, enzyme selectivity, and cellular effects. J Med Chem. 2003 Jan 16;46(2):222-36.
• [22] A systematic interaction map of validated kinase inhibitors with Ser/Thr kinases. Proc Natl Acad Sci U S A. 2007 Dec 18;104(51):20523-8.
• [23] 1-Azakenpaullone is a selective inhibitor of glycogen synthase kinase-3 beta. Bioorg Med Chem Lett. 2004 Jan 19;14(2):413-6.
• [24] A 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.
• [25] 1-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.
• [26] 2,6,9-trisubstituted purines: optimization towards highly potent and selective CDK1 inhibitors. Bioorg Med Chem Lett. 1999 Jan 4;9(1):91-6.
• [27] M-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.
• [28] The kinase inhibitor indirubin-3'-oxime prevents germinal vesicle breakdown and reduces parthenogenetic development of pig oocytes. Theriogenology. 2006 Mar 1;65(4):744-56.
• [29] How many drug targets are there Nat Rev Drug Discov. 2006 Dec;5(12):993-6.
• [30] Synthesis and evaluation of N-acyl sulfonamides as potential prodrugs of cyclin-dependent kinase inhibitor JNJ-7706621. Bioorg Med Chem Lett. 2006 Jul 15;16(14):3639-41.
• [31] Synthesis, structure-activity relationship, and biological studies of indolocarbazoles as potent cyclin D1-CDK4 inhibitors. J Med Chem. 2003 May 22;46(11):2027-30.
• [32] Microxine, a new cdc2 kinase inhibitor from the Australian marine sponge Microxina species. J Nat Prod. 2001 Apr;64(4):525-6.
• [33] Potentiation 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.
• [34] Cellular characterization of a novel focal adhesion kinase inhibitor. J Biol Chem. 2007 May 18;282(20):14845-52.
• [35] Imidazole pyrimidine amides as potent, orally bioavailable cyclin-dependent kinase inhibitors. Bioorg Med Chem Lett. 2008 Dec 15;18(24):6486-9.
• [36] First Cdc7 kinase inhibitors: pyrrolopyridinones as potent and orally active antitumor agents. 2. Lead discovery. J Med Chem. 2009 Jan 22;52(2):293-307.
• [37] SU9516: biochemical analysis of cdk inhibition and crystal structure in complex with cdk2. Biochem Biophys Res Commun. 2003 Oct 24;310(3):1026-31.