Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TT7HF4W)

• DTT Name: Cyclin-dependent kinase 2 (CDK2)
• Synonyms: Sin3 associated polypeptide; SIN3-associated protein; P33 protein kinase; Cell division protein kinase 2; CDKN2
• Gene Name: CDK2
• DTT Type: Clinical trial target; [1]
• BioChemical Class: Kinase
• UniProt ID: CDK2_HUMAN
• TTD ID: T70176
• EC Number: EC 2.7.11.22
• Sequence:
  MENFQKVEKIGEGTYGVVYKARNKLTGEVVALKKIRLDTETEGVPSTAIREISLLKELNH
  PNIVKLLDVIHTENKLYLVFEFLHQDLKKFMDASALTGIPLPLIKSYLFQLLQGLAFCHS
  HRVLHRDLKPQNLLINTEGAIKLADFGLARAFGVPVRTYTHEVVTLWYRAPEILLGCKYY
  STAVDIWSLGCIFAEMVTRRALFPGDSEIDQLFRIFRTLGTPDEVVWPGVTSMPDYKPSF
  PKWARQDFSKVVPPLDEDGRSLLSQMLHYDPNKRISAKAALAHPFFQDVTKPVPHLRL
• Function: Phosphorylates CTNNB1, USP37, p53/TP53, NPM1, CDK7, RB1, BRCA2, MYC, NPAT, EZH2. Triggers duplication of centrosomes and DNA. Acts at the G1-S transition to promote the E2F transcriptional program and the initiation of DNA synthesis, and modulates G2 progression; controls the timing of entry into mitosis/meiosis by controlling the subsequent activation of cyclin B/CDK1 by phosphorylation, and coordinates the activation of cyclin B/CDK1 at the centrosome and in the nucleus. Crucial role in orchestrating a fine balance between cellular proliferation, cell death, and DNA repair in human embryonic stem cells (hESCs). Activity of CDK2 is maximal during S phase and G2; activated by interaction with cyclin E during the early stages of DNA synthesis to permit G1-S transition, and subsequently activated by cyclin A2 (cyclin A1 in germ cells) during the late stages of DNA replication to drive the transition from S phase to mitosis, the G2 phase. EZH2 phosphorylation promotes H3K27me3 maintenance and epigenetic gene silencing. Phosphorylates CABLES1. Cyclin E/CDK2 prevents oxidative stress-mediated Ras-induced senescence by phosphorylating MYC. Involved in G1-S phase DNA damage checkpoint that prevents cells with damaged DNA from initiating mitosis; regulates homologous recombination-dependent repair by phosphorylating BRCA2, this phosphorylation is low in S phase when recombination is active, but increases as cells progress towards mitosis. In response to DNA damage, double-strand break repair by homologous recombination a reduction of CDK2-mediated BRCA2 phosphorylation. Phosphorylation of RB1 disturbs its interaction with E2F1. NPM1 phosphorylation by cyclin E/CDK2 promotes its dissociates from unduplicated centrosomes, thus initiating centrosome duplication. Cyclin E/CDK2-mediated phosphorylation of NPAT at G1-S transition and until prophase stimulates the NPAT-mediated activation of histone gene transcription during S phase. Required for vitamin D-mediated growth inhibition by being itself inactivated. Involved in the nitric oxide- (NO) mediated signaling in a nitrosylation/activation-dependent manner. USP37 is activated by phosphorylation and thus triggers G1-S transition. CTNNB1 phosphorylation regulates insulin internalization. Phosphorylates FOXP3 and negatively regulates its transcriptional activity and protein stability. Phosphorylates CDK2AP2. Serine/threonine-protein kinase involved in the control of the cell cycle; essential for meiosis, but dispensable for mitosis.
• KEGG Pathway:
  FoxO signaling pathway (hsa04068)
  Cell cycle (hsa04110)
  Oocyte meiosis (hsa04114)
  p53 signaling pathway (hsa04115)
  PI3K-Akt signaling pathway (hsa04151)
  Progesterone-mediated oocyte maturation (hsa04914)
  Hepatitis B (hsa05161)
  Measles (hsa05162)
  Herpes simplex infection (hsa05168)
  Epstein-Barr virus infection (hsa05169)
  Pathways in cancer (hsa05200)
  Viral carcinogenesis (hsa05203)
  Prostate cancer (hsa05215)
  Small cell lung cancer (hsa05222)
• Reactome Pathway:
  Activation of ATR in response to replication stress (R-HSA-176187)
  Regulation of APC/C activators between G1/S and early anaphase (R-HSA-176408)
  SCF(Skp2)-mediated degradation of p27/p21 (R-HSA-187577)
  Senescence-Associated Secretory Phenotype (SASP) (R-HSA-2559582)
  DNA Damage/Telomere Stress Induced Senescence (R-HSA-2559586)
  Processing of DNA double-strand break ends (R-HSA-5693607)
  G2 Phase (R-HSA-68911)
  Orc1 removal from chromatin (R-HSA-68949)
  Cyclin E associated events during G1/S transition (R-HSA-69202)
  Cyclin A/B1 associated events during G2/M transition (R-HSA-69273)
  p53-Dependent G1 DNA Damage Response (R-HSA-69563)
  Cyclin A (R-HSA-69656)
  Meiotic recombination (R-HSA-912446)
  Factors involved in megakaryocyte development and platelet production (R-HSA-983231)
  G0 and Early G1 (R-HSA-1538133)

Molecular Interaction Atlas (MIA) of This DTT

15 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
PHA848125	DMS2Q9G	Thymic cancer	2C27	Phase 2	[2]
R-roscovitine	DMSH108	Non-small-cell lung cancer	2C25.Y	Phase 2	[3]
Ro 31-7453	DM83QCL	Solid tumour/cancer	2A00-2F9Z	Phase 2	[4]
NUV-422	DMQJQNT	Malignant glioma	2A00.0	Phase 1/2	[5]
TG02	DMZFIGQ	Anaplastic astrocytoma	2A00.0	Phase 1/2	[6]
AG-024322	DMY4WVK	Solid tumour/cancer	2A00-2F9Z	Phase 1	[3]
AT7519	DMCE08M	Solid tumour/cancer	2A00-2F9Z	Phase 1	[7]
AZD-5438	DMBQ2TF	Solid tumour/cancer	2A00-2F9Z	Phase 1	[8]
CYC065	DM9ODT6	Lymphoma	2A80-2A86	Phase 1	[9]
FN-1501	DM7BMD6	Solid tumour/cancer	2A00-2F9Z	Phase 1	[10]
PF-07104091	DMMJZ2E	Non-small-cell lung cancer	2C25	Phase 1	[11]
PHA-793887	DM2Y4FG	Solid tumour/cancer	2A00-2F9Z	Phase 1	[12]
RGB-286638	DMEGOQP	Haematological malignancy	2B33.Y	Phase 1	[13]
RGT-419B	DMD2MND	Breast cancer	2C60-2C65	Phase 1	[14]
SNS-032	DMEITAS	Solid tumour/cancer	2A00-2F9Z	Phase 1	[15]

27 Patented Agent(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
1,5-di-substituted pyridine derivative 1	DMEUO8G	N. A.	N. A.	Patented	[16]
4-(thiazol-5-yl)-pyrimidine derivative 1	DM7B81V	N. A.	N. A.	Patented	[16]
4-(thiazol-5-yl)-pyrimidine derivative 2	DMMQFCN	N. A.	N. A.	Patented	[16]
4-amino-3,5-di-substituted-thiazole derivative 1	DMMELYI	N. A.	N. A.	Patented	[16]
5-fluoro-N-(pyridin-2-yl)pyridin-2-amine derivative 1	DMHXKFB	N. A.	N. A.	Patented	[16]
Alkyl sulfone derivative 1	DM06U3J	N. A.	N. A.	Patented	[16]
Aniline derivative 1	DMDSUGF	N. A.	N. A.	Patented	[16]
Diamidothiazole derivative 1	DM02V5Q	N. A.	N. A.	Patented	[16]
Diaryl amine derivative 1	DM06MJH	N. A.	N. A.	Patented	[16]
Flavopiridol analog 1	DMXL3A5	N. A.	N. A.	Patented	[16]
Fluorinated compound 1	DMGOSN2	N. A.	N. A.	Patented	[16]
Indole-based analog 11	DMVRX7S	N. A.	N. A.	Patented	[16]
Indole-based analog 13	DMV7DFM	N. A.	N. A.	Patented	[16]
Isoquinoline 1,3-dione derivative 1	DMIYUAN	N. A.	N. A.	Patented	[16]
Isosteric imidazolyl pyrimidine derivative 1	DMP2QDM	N. A.	N. A.	Patented	[16]
N-(pyridin-2-yl)pyridine methylsulfone derivative 1	DM305UL	N. A.	N. A.	Patented	[16]
N-(pyridin-2-yl)pyrimidin-4-amine derivative 2	DMTZ6K9	N. A.	N. A.	Patented	[16]
N-phenyl-pyrimidin-4-amine derivative 1	DMAV8LM	N. A.	N. A.	Patented	[16]
Naphthyridine and isoquinoline derivative 1	DMTGIP7	N. A.	N. A.	Patented	[16]
Nitrogen mustard derivative 1	DMXDSYU	N. A.	N. A.	Patented	[16]
Oxazolyl methylthiothiazole derivative 1	DMZM6FW	N. A.	N. A.	Patented	[16]
PMID25991433-Compound-A1	DM89LF0	N. A.	N. A.	Patented	[17]
PMID26161698-Compound-25	DM4AFHY	N. A.	N. A.	Patented	[16]
Pyrazolo-triazine derivative 2	DML6V78	N. A.	N. A.	Patented	[16]
Pyrazolo[1,5-a]-1,3,5-triazine derivative 1	DMOK7CW	N. A.	N. A.	Patented	[16]
Pyrrolo[2,3-d]pyrimidine derivative 9	DM0HU5O	N. A.	N. A.	Patented	[16]
Roscovitine derivative 1	DMD1G3Z	N. A.	N. A.	Patented	[16]

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	[3]
BAY 10-00394	DMV2DIW	Small-cell lung cancer	2C25.Y	Discontinued in Phase 2	[18]
R547	DMK25FU	Advanced solid tumour	2A00-2F9Z	Discontinued in Phase 1	[3]
ZK 304709	DMJ9R4A	Advanced solid tumour	2A00-2F9Z	Discontinued in Phase 1	[3]
Olomoucine	DMNAFG1	N. A.	N. A.	Terminated	[20]
PD-0183812	DMWYP86	Retinoblastoma	2D02.2	Terminated	[21]

2 Preclinical Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
INOC-005	DMBQGZ9	Solid tumour/cancer	2A00-2F9Z	Preclinical	[19]
L-751250	DMOERXK	Obesity	5B81	Preclinical	[20]

87 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
(2'Z,3'E)-5-Chloro-5'-chloro-indirubin-3'-oxime	DMGXRSZ	Discovery agent	N.A.	Investigative	[22]
(2'Z,3'E)-5-Chloro-5'-fluoro-indirubin-3'-oxime	DM6AUHR	Discovery agent	N.A.	Investigative	[22]
(2'Z,3'E)-5-Chloro-5'-hydroxy-indirubin-3'-oxime	DMD7WGM	Discovery agent	N.A.	Investigative	[22]
(2'Z,3'E)-5-Chloro-5'-methyl-indirubin-3'-oxime	DMZ0V6G	Discovery agent	N.A.	Investigative	[22]
(2'Z,3'E)-5-Fluoro-5'-chloro-indirubin-3'-oxime	DMO7RFL	Discovery agent	N.A.	Investigative	[22]
(2'Z,3'E)-5-Fluoro-5'-fluoro-indirubin-3'-oxime	DMJ4ABD	Discovery agent	N.A.	Investigative	[22]
(2'Z,3'E)-5-Fluoro-5'-hydroxy-indirubin-3'-oxime	DM9LQH1	Discovery agent	N.A.	Investigative	[22]
(2'Z,3'E)-5-Fluoro-5'-methoxy-indirubin-3'-oxime	DMQDH3N	Discovery agent	N.A.	Investigative	[22]
(2'Z,3'E)-5-Fluoro-5'-methyl-indirubin-3'-oxime	DMAS3JC	Discovery agent	N.A.	Investigative	[22]
(2'Z,3'E)-5-Nitro-5'-chloro-indirubin-3'-oxime	DMYLX0U	Discovery agent	N.A.	Investigative	[22]
(2'Z,3'E)-5-Nitro-5'-fluoro-indirubin-3'-oxime	DMXZ2UC	Discovery agent	N.A.	Investigative	[22]
(2'Z,3'E)-5-Nitro-5'-hydroxy-indirubin-3'-oxime	DM0S82C	Discovery agent	N.A.	Investigative	[22]
(2'Z,3'E)-5-Nitro-5'-methoxy-indirubin-3'-oxime	DMLOIUK	Discovery agent	N.A.	Investigative	[22]
(2'Z,3'E)-5-Nitro-5'-methyl-indirubin-3'-oxime	DM6BA5L	Discovery agent	N.A.	Investigative	[22]
1-Amino-6-Cyclohex-3-Enylmethyloxypurine	DM6AV2S	Discovery agent	N.A.	Investigative	[23]
10Z-Hymenialdisine	DMIRSA5	Discovery agent	N.A.	Investigative	[20]
2-((3,5-diamino-1H-pyrazol-4-yl)diazenyl)phenol	DM1BI65	Discovery agent	N.A.	Investigative	[24]
2-Amino-6-Chloropyrazine	DMJVG30	Discovery agent	N.A.	Investigative	[23]
2-ANILINO-6-CYCLOHEXYLMETHOXYPURINE	DMFNEZW	Discovery agent	N.A.	Investigative	[25]
3,4-di-(4-methoxyphenyl)-1H-pyrrole-2,5-dione	DMDO175	Discovery agent	N.A.	Investigative	[26]
3,4-diphenyl-1H-pyrrole-2,5-dione	DMPK6YT	Discovery agent	N.A.	Investigative	[26]
3-((3,5-diamino-1H-pyrazol-4-yl)diazenyl)phenol	DMJZK40	Discovery agent	N.A.	Investigative	[24]
3-(4-methoxyphenyl)-4-phenyl-1H-pyrrole-2,5-dione	DMGC7RY	Discovery agent	N.A.	Investigative	[26]
3-(indole-3-yl)-4-phenyl-1H-pyrrole-2,5-dione	DM3EV9N	Discovery agent	N.A.	Investigative	[26]
4-(2,4-Dimethyl-Thiazol-5-Yl)-Pyrimidin-2-Ylamine	DME8BLW	Discovery agent	N.A.	Investigative	[23]
4-[(3,5-diamino-1H-pyrazol-4-yl)diazenyl]phenol	DMSKJ1X	Discovery agent	N.A.	Investigative	[24]
4-[(6-chloropyrazin-2-yl)amino]benzenesulfonamide	DMGRWEU	Discovery agent	N.A.	Investigative	[25]
4-[3-Hydroxyanilino]-6,7-Dimethoxyquinazoline	DMTIA27	Discovery agent	N.A.	Investigative	[27]
5-hydroxynaphthalene-1-sulfonamide	DMMF57V	Discovery agent	N.A.	Investigative	[25]
5-nitroindirubin-3'-oxime	DM4K8N2	Discovery agent	N.A.	Investigative	[22]
6-(3-Amino-benzyloxy)-9H-purin-2-ylamine	DMJ92W0	Discovery agent	N.A.	Investigative	[28]
6-(3-Methyl-benzyloxy)-9H-purin-2-ylamine	DMSW3KN	Discovery agent	N.A.	Investigative	[28]
6-(Cyclohex-3-enylmethoxy)-9H-purin-2-ylamine	DMAYWIN	Discovery agent	N.A.	Investigative	[28]
6-CYCLOHEXYLMETHOXY-2-(3'-CHLOROANILINO) PURINE	DMACTDZ	Discovery agent	N.A.	Investigative	[25]
6-Cyclohexylmethoxy-pyrimidine-2,4,5-triamine	DM9IHYS	Discovery agent	N.A.	Investigative	[29]
6-cyclohexylmethyloxy-2-(4'-hydroxyanilino)purine	DM6UP25	Discovery agent	N.A.	Investigative	[25]
6-O-Cyclohexylmethyl Guanine	DMDIW08	Discovery agent	N.A.	Investigative	[23]
9-Nitropaullone	DM8LUYM	Discovery agent	N.A.	Investigative	[20]
aloisine	DM7HGX8	Discovery agent	N.A.	Investigative	[30]
aloisine A	DM5U1LN	Discovery agent	N.A.	Investigative	[31]
aminopurvalanol A	DMKLC3O	N. A.	N. A.	Investigative	[32]
Benzyl-(9-isopropyl-9H-purin-6-yl)-amine	DMNE1M3	Discovery agent	N.A.	Investigative	[33]
BMS-265246	DM6LPIG	Discovery agent	N.A.	Investigative	[34]
BMS-536924	DMXJB4N	Discovery agent	N.A.	Investigative	[35]
BOHEMINE	DMLCMA3	Discovery agent	N.A.	Investigative	[33]
BX-795	DMRIMLJ	Discovery agent	N.A.	Investigative	[36]
BX-912	DMZA45C	Discovery agent	N.A.	Investigative	[36]
Cdk1/2 inhibitor III	DMS62T0	Discovery agent	N.A.	Investigative	[37]
Cdk4 inhibitor III	DMNZJAX	Discovery agent	N.A.	Investigative	[38]
CVT-313	DMSEK5W	Discovery agent	N.A.	Investigative	[39]
Double Oxidized Cysteine	DM6TU84	Discovery agent	N.A.	Investigative	[23]
GW-8510	DML4UMT	Discovery agent	N.A.	Investigative	[40]
Indirubin-3'-monoxime	DMLRQH0	Discovery agent	N.A.	Investigative	[20]
Indirubin-5-sulfonate	DM08VHZ	Discovery agent	N.A.	Investigative	[20]
JNJ-7706621	DMHTYBS	Discovery agent	N.A.	Investigative	[41]
K00024	DMP8M9Q	Discovery agent	N.A.	Investigative	[42]
Lysine Nz-Carboxylic Acid	DMW1YK3	Discovery agent	N.A.	Investigative	[23]
MERIOLIN 1	DMJT93H	Discovery agent	N.A.	Investigative	[43]
MERIOLIN 2	DM413XJ	Discovery agent	N.A.	Investigative	[43]
MERIOLIN 3	DMVE95S	Discovery agent	N.A.	Investigative	[43]
MERIOLIN 4	DMIJMZQ	Discovery agent	N.A.	Investigative	[43]
MERIOLIN 5	DMGVLR0	Discovery agent	N.A.	Investigative	[43]
MERIOLIN 6	DMW5AXC	Discovery agent	N.A.	Investigative	[43]
MERIOLIN 8	DM0E95B	Discovery agent	N.A.	Investigative	[43]
N-(3-METHYLBUT-2-EN-1-YL)-9H-PURIN-6-AMINE	DM2D4KY	Discovery agent	N.A.	Investigative	[25]
N-(4-amino-5-cyano-6-phenylpyridin-2-yl)acetamide	DMUFVM6	Discovery agent	N.A.	Investigative	[44]
N-(4-sulfamoylphenyl)-1H-indazole-3-carboxamide	DMOMYDV	Discovery agent	N.A.	Investigative	[25]
N-(5-Cyclopropyl-1h-Pyrazol-3-Yl)Benzamide	DM9JCD3	Discovery agent	N.A.	Investigative	[23]
N-phenyl-1H-pyrazole-3-carboxamide	DMP5E1G	Discovery agent	N.A.	Investigative	[25]
NSC-625987	DMLG05U	Discovery agent	N.A.	Investigative	[45]
NU-6027	DMELYAX	Discovery agent	N.A.	Investigative	[29]
NU-6102	DMMOFKD	Discovery agent	N.A.	Investigative	[46]
NU6140	DMCUSG3	Discovery agent	N.A.	Investigative	[47]
Oxindole 95	DM4UL1G	Discovery agent	N.A.	Investigative	[20]
PF-228	DM32FKD	Discovery agent	N.A.	Investigative	[48]
PHA-690509	DMNS70E	Solid tumour/cancer	2A00-2F9Z	Investigative	[49]
PHENYLAMINOIMIDAZO(1,2-ALPHA)PYRIDINE	DMHVW61	Discovery agent	N.A.	Investigative	[25]
PMID18986805C9b	DMFU6AI	Discovery agent	N.A.	Investigative	[50]
PMID19115845C89S	DMB9F2L	Discovery agent	N.A.	Investigative	[51]
Purvalanol A	DMNQ7TM	Discovery agent	N.A.	Investigative	[52]
PYRAZOLOPYRIDAZINE 1	DMKTB5U	Discovery agent	N.A.	Investigative	[53]
PYRAZOLOPYRIDAZINE 2	DMI7AUJ	Discovery agent	N.A.	Investigative	[53]
RESCOVITINE	DM2IBND	Discovery agent	N.A.	Investigative	[54]
SCH-546909	DMMXIB4	Solid tumour/cancer	2A00-2F9Z	Investigative	[39]
SU9516	DMQHG0R	Discovery agent	N.A.	Investigative	[20]
TRIAZOLOPYRIMIDINE	DM5ZBF3	Discovery agent	N.A.	Investigative	[25]
VER-54505	DMYD7P5	Solid tumour/cancer	2A00-2F9Z	Investigative	[39]

Molecular Expression Atlas (MEA) of This DTT

Disease Name	ICD 11	Studied Tissue	p-value	Fold-Change	Z-score
Lung cancer	2C82	Lung tissue	2.28E-06	0.12	0.19
Retinoblastoma	2C82	Uvea	9.54E-13	5.05	15.31
Psoriasis	EA90	Skin	3.41E-08	-0.44	-0.67

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