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]
• Related Disease:
  Thymoma [ICD-11: 2C27]
  Brain cancer [ICD-11: 2A00]
  Breast cancer [ICD-11: 2C60-2C6Y]
  Lung cancer [ICD-11: 2C25]
  Lymphoma [ICD-11: 2A80-2A86]
  Malignant haematopoietic neoplasm [ICD-11: 2B33]
  Non-small cell lung cancer [ICD-11: 2C25]
  Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• 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

13 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], [3]
R-roscovitine	DMSH108	Non-small-cell lung cancer	2C25.Y	Phase 2	[4], [5], [6]
Ro 31-7453	DM83QCL	Solid tumour/cancer	2A00-2F9Z	Phase 2	[5]
TG02	DMZFIGQ	Anaplastic astrocytoma	2A00.0	Phase 1/2	[7]
AG-024322	DMY4WVK	Solid tumour/cancer	2A00-2F9Z	Phase 1	[4]
AT7519	DMCE08M	Solid tumour/cancer	2A00-2F9Z	Phase 1	[8]
AZD-5438	DMBQ2TF	Solid tumour/cancer	2A00-2F9Z	Phase 1	[9], [10]
CYC065	DM9ODT6	Lymphoma	2A80-2A86	Phase 1	[11]
FN-1501	DM7BMD6	Solid tumour/cancer	2A00-2F9Z	Phase 1	[12]
PF-07104091	DMMJZ2E	Non-small cell lung cancer	2C25	Phase 1	[13]
PHA-793887	DM2Y4FG	Solid tumour/cancer	2A00-2F9Z	Phase 1	[14]
RGB-286638	DMEGOQP	Haematological malignancy	2B33.Y	Phase 1	[15]
SNS-032	DMEITAS	Solid tumour/cancer	2A00-2F9Z	Phase 1	[16], [17]

28 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	[18]
4-(thiazol-5-yl)-pyrimidine derivative 1	DM7B81V	N. A.	N. A.	Patented	[18]
4-(thiazol-5-yl)-pyrimidine derivative 2	DMMQFCN	N. A.	N. A.	Patented	[18]
4-amino-3,5-di-substituted-thiazole derivative 1	DMMELYI	N. A.	N. A.	Patented	[18]
5-fluoro-N-(pyridin-2-yl)pyridin-2-amine derivative 1	DMHXKFB	N. A.	N. A.	Patented	[18]
Alkyl sulfone derivative 1	DM06U3J	N. A.	N. A.	Patented	[18]
Aniline derivative 1	DMDSUGF	N. A.	N. A.	Patented	[18]
Diamidothiazole derivative 1	DM02V5Q	N. A.	N. A.	Patented	[18]
Diaryl amine derivative 1	DM06MJH	N. A.	N. A.	Patented	[18]
Flavopiridol analog 1	DMXL3A5	N. A.	N. A.	Patented	[18]
Fluorinated compound 1	DMGOSN2	N. A.	N. A.	Patented	[18]
Indole-based analog 11	DMVRX7S	N. A.	N. A.	Patented	[18]
Indole-based analog 13	DMV7DFM	N. A.	N. A.	Patented	[18]
Isoquinoline 1,3-dione derivative 1	DMIYUAN	N. A.	N. A.	Patented	[18]
Isosteric imidazolyl pyrimidine derivative 1	DMP2QDM	N. A.	N. A.	Patented	[18]
N-(pyridin-2-yl)pyridine methylsulfone derivative 1	DM305UL	N. A.	N. A.	Patented	[18]
N-(pyridin-2-yl)pyrimidin-4-amine derivative 2	DMTZ6K9	N. A.	N. A.	Patented	[18]
N-phenyl-pyrimidin-4-amine derivative 1	DMAV8LM	N. A.	N. A.	Patented	[18]
Naphthyridine and isoquinoline derivative 1	DMTGIP7	N. A.	N. A.	Patented	[18]
Nitrogen mustard derivative 1	DMXDSYU	N. A.	N. A.	Patented	[18]
Oxazolyl methylthiothiazole derivative 1	DMZM6FW	N. A.	N. A.	Patented	[18]
Palbociclib/ribociclib analog 1	DM0RI7F	N. A.	N. A.	Patented	[18]
PMID25991433-Compound-A1	DM89LF0	N. A.	N. A.	Patented	[19]
PMID26161698-Compound-25	DM4AFHY	N. A.	N. A.	Patented	[18]
Pyrazolo-triazine derivative 2	DML6V78	N. A.	N. A.	Patented	[18]
Pyrazolo[1,5-a]-1,3,5-triazine derivative 1	DMOK7CW	N. A.	N. A.	Patented	[18]
Pyrrolo[2,3-d]pyrimidine derivative 9	DM0HU5O	N. A.	N. A.	Patented	[18]
Roscovitine derivative 1	DMD1G3Z	N. A.	N. A.	Patented	[18]

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	[4]
BAY 10-00394	DMV2DIW	Small-cell lung cancer	2C25.Y	Discontinued in Phase 2	[20]
R547	DMK25FU	Advanced solid tumour	2A00-2F9Z	Discontinued in Phase 1	[4]
ZK 304709	DMJ9R4A	Advanced solid tumour	2A00-2F9Z	Discontinued in Phase 1	[4]
Olomoucine	DMNAFG1	N. A.	N. A.	Terminated	[22]
PD-0183812	DMWYP86	Retinoblastoma	2D02.2	Terminated	[23]

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	[21]
L-751250	DMOERXK	Obesity	5B81	Preclinical	[22]

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	[24]
(2'Z,3'E)-5-Chloro-5'-fluoro-indirubin-3'-oxime	DM6AUHR	Discovery agent	N.A.	Investigative	[24]
(2'Z,3'E)-5-Chloro-5'-hydroxy-indirubin-3'-oxime	DMD7WGM	Discovery agent	N.A.	Investigative	[24]
(2'Z,3'E)-5-Chloro-5'-methyl-indirubin-3'-oxime	DMZ0V6G	Discovery agent	N.A.	Investigative	[24]
(2'Z,3'E)-5-Fluoro-5'-chloro-indirubin-3'-oxime	DMO7RFL	Discovery agent	N.A.	Investigative	[24]
(2'Z,3'E)-5-Fluoro-5'-fluoro-indirubin-3'-oxime	DMJ4ABD	Discovery agent	N.A.	Investigative	[24]
(2'Z,3'E)-5-Fluoro-5'-hydroxy-indirubin-3'-oxime	DM9LQH1	Discovery agent	N.A.	Investigative	[24]
(2'Z,3'E)-5-Fluoro-5'-methoxy-indirubin-3'-oxime	DMQDH3N	Discovery agent	N.A.	Investigative	[24]
(2'Z,3'E)-5-Fluoro-5'-methyl-indirubin-3'-oxime	DMAS3JC	Discovery agent	N.A.	Investigative	[24]
(2'Z,3'E)-5-Nitro-5'-chloro-indirubin-3'-oxime	DMYLX0U	Discovery agent	N.A.	Investigative	[24]
(2'Z,3'E)-5-Nitro-5'-fluoro-indirubin-3'-oxime	DMXZ2UC	Discovery agent	N.A.	Investigative	[24]
(2'Z,3'E)-5-Nitro-5'-hydroxy-indirubin-3'-oxime	DM0S82C	Discovery agent	N.A.	Investigative	[24]
(2'Z,3'E)-5-Nitro-5'-methoxy-indirubin-3'-oxime	DMLOIUK	Discovery agent	N.A.	Investigative	[24]
(2'Z,3'E)-5-Nitro-5'-methyl-indirubin-3'-oxime	DM6BA5L	Discovery agent	N.A.	Investigative	[24]
1-Amino-6-Cyclohex-3-Enylmethyloxypurine	DM6AV2S	Discovery agent	N.A.	Investigative	[25]
10Z-Hymenialdisine	DMIRSA5	Discovery agent	N.A.	Investigative	[22]
2-((3,5-diamino-1H-pyrazol-4-yl)diazenyl)phenol	DM1BI65	Discovery agent	N.A.	Investigative	[26]
2-Amino-6-Chloropyrazine	DMJVG30	Discovery agent	N.A.	Investigative	[25]
2-ANILINO-6-CYCLOHEXYLMETHOXYPURINE	DMFNEZW	Discovery agent	N.A.	Investigative	[27], [28]
3,4-di-(4-methoxyphenyl)-1H-pyrrole-2,5-dione	DMDO175	Discovery agent	N.A.	Investigative	[29]
3,4-diphenyl-1H-pyrrole-2,5-dione	DMPK6YT	Discovery agent	N.A.	Investigative	[29]
3-((3,5-diamino-1H-pyrazol-4-yl)diazenyl)phenol	DMJZK40	Discovery agent	N.A.	Investigative	[26]
3-(4-methoxyphenyl)-4-phenyl-1H-pyrrole-2,5-dione	DMGC7RY	Discovery agent	N.A.	Investigative	[29]
3-(indole-3-yl)-4-phenyl-1H-pyrrole-2,5-dione	DM3EV9N	Discovery agent	N.A.	Investigative	[29]
4-(2,4-Dimethyl-Thiazol-5-Yl)-Pyrimidin-2-Ylamine	DME8BLW	Discovery agent	N.A.	Investigative	[25]
4-[(3,5-diamino-1H-pyrazol-4-yl)diazenyl]phenol	DMSKJ1X	Discovery agent	N.A.	Investigative	[26]
4-[(6-chloropyrazin-2-yl)amino]benzenesulfonamide	DMGRWEU	Discovery agent	N.A.	Investigative	[27]
4-[3-Hydroxyanilino]-6,7-Dimethoxyquinazoline	DMTIA27	Discovery agent	N.A.	Investigative	[30]
5-hydroxynaphthalene-1-sulfonamide	DMMF57V	Discovery agent	N.A.	Investigative	[27]
5-nitroindirubin-3'-oxime	DM4K8N2	Discovery agent	N.A.	Investigative	[24]
6-(3-Amino-benzyloxy)-9H-purin-2-ylamine	DMJ92W0	Discovery agent	N.A.	Investigative	[31]
6-(3-Methyl-benzyloxy)-9H-purin-2-ylamine	DMSW3KN	Discovery agent	N.A.	Investigative	[31]
6-(Cyclohex-3-enylmethoxy)-9H-purin-2-ylamine	DMAYWIN	Discovery agent	N.A.	Investigative	[31]
6-CYCLOHEXYLMETHOXY-2-(3'-CHLOROANILINO) PURINE	DMACTDZ	Discovery agent	N.A.	Investigative	[27]
6-Cyclohexylmethoxy-pyrimidine-2,4,5-triamine	DM9IHYS	Discovery agent	N.A.	Investigative	[32]
6-cyclohexylmethyloxy-2-(4'-hydroxyanilino)purine	DM6UP25	Discovery agent	N.A.	Investigative	[27], [28]
6-O-Cyclohexylmethyl Guanine	DMDIW08	Discovery agent	N.A.	Investigative	[25], [33]
9-Nitropaullone	DM8LUYM	Discovery agent	N.A.	Investigative	[22]
aloisine	DM7HGX8	Discovery agent	N.A.	Investigative	[34]
aloisine A	DM5U1LN	Discovery agent	N.A.	Investigative	[35]
aminopurvalanol A	DMKLC3O	N. A.	N. A.	Investigative	[36]
Benzyl-(9-isopropyl-9H-purin-6-yl)-amine	DMNE1M3	Discovery agent	N.A.	Investigative	[37]
BMS-265246	DM6LPIG	Discovery agent	N.A.	Investigative	[38]
BMS-536924	DMXJB4N	Discovery agent	N.A.	Investigative	[39]
BOHEMINE	DMLCMA3	Discovery agent	N.A.	Investigative	[37]
BX-795	DMRIMLJ	Discovery agent	N.A.	Investigative	[40]
BX-912	DMZA45C	Discovery agent	N.A.	Investigative	[40]
Cdk1/2 inhibitor III	DMS62T0	Discovery agent	N.A.	Investigative	[41]
Cdk4 inhibitor III	DMNZJAX	Discovery agent	N.A.	Investigative	[42]
CVT-313	DMSEK5W	Discovery agent	N.A.	Investigative	[43]
Double Oxidized Cysteine	DM6TU84	Discovery agent	N.A.	Investigative	[25]
GW-8510	DML4UMT	Discovery agent	N.A.	Investigative	[44]
Indirubin-3'-monoxime	DMLRQH0	Discovery agent	N.A.	Investigative	[22]
Indirubin-5-sulfonate	DM08VHZ	Discovery agent	N.A.	Investigative	[22]
JNJ-7706621	DMHTYBS	Discovery agent	N.A.	Investigative	[45]
K00024	DMP8M9Q	Discovery agent	N.A.	Investigative	[46]
Lysine Nz-Carboxylic Acid	DMW1YK3	Discovery agent	N.A.	Investigative	[25]
MERIOLIN 1	DMJT93H	Discovery agent	N.A.	Investigative	[47]
MERIOLIN 2	DM413XJ	Discovery agent	N.A.	Investigative	[47]
MERIOLIN 3	DMVE95S	Discovery agent	N.A.	Investigative	[47]
MERIOLIN 4	DMIJMZQ	Discovery agent	N.A.	Investigative	[47]
MERIOLIN 5	DMGVLR0	Discovery agent	N.A.	Investigative	[47]
MERIOLIN 6	DMW5AXC	Discovery agent	N.A.	Investigative	[47]
MERIOLIN 8	DM0E95B	Discovery agent	N.A.	Investigative	[47]
N-(3-METHYLBUT-2-EN-1-YL)-9H-PURIN-6-AMINE	DM2D4KY	Discovery agent	N.A.	Investigative	[27]
N-(4-amino-5-cyano-6-phenylpyridin-2-yl)acetamide	DMUFVM6	Discovery agent	N.A.	Investigative	[48]
N-(4-sulfamoylphenyl)-1H-indazole-3-carboxamide	DMOMYDV	Discovery agent	N.A.	Investigative	[27]
N-(5-Cyclopropyl-1h-Pyrazol-3-Yl)Benzamide	DM9JCD3	Discovery agent	N.A.	Investigative	[25]
N-phenyl-1H-pyrazole-3-carboxamide	DMP5E1G	Discovery agent	N.A.	Investigative	[27]
NSC-625987	DMLG05U	Discovery agent	N.A.	Investigative	[49]
NU-6027	DMELYAX	Discovery agent	N.A.	Investigative	[32]
NU-6102	DMMOFKD	Discovery agent	N.A.	Investigative	[50]
NU6140	DMCUSG3	Discovery agent	N.A.	Investigative	[51]
Oxindole 95	DM4UL1G	Discovery agent	N.A.	Investigative	[22]
PF-228	DM32FKD	Discovery agent	N.A.	Investigative	[52]
PHA-690509	DMNS70E	Solid tumour/cancer	2A00-2F9Z	Investigative	[53]
PHENYLAMINOIMIDAZO(1,2-ALPHA)PYRIDINE	DMHVW61	Discovery agent	N.A.	Investigative	[27]
PMID18986805C9b	DMFU6AI	Discovery agent	N.A.	Investigative	[54]
PMID19115845C89S	DMB9F2L	Discovery agent	N.A.	Investigative	[55]
Purvalanol A	DMNQ7TM	Discovery agent	N.A.	Investigative	[56]
PYRAZOLOPYRIDAZINE 1	DMKTB5U	Discovery agent	N.A.	Investigative	[57]
PYRAZOLOPYRIDAZINE 2	DMI7AUJ	Discovery agent	N.A.	Investigative	[57]
RESCOVITINE	DM2IBND	Discovery agent	N.A.	Investigative	[58]
SCH-546909	DMMXIB4	Solid tumour/cancer	2A00-2F9Z	Investigative	[43]
SU9516	DMQHG0R	Discovery agent	N.A.	Investigative	[22]
TRIAZOLOPYRIMIDINE	DM5ZBF3	Discovery agent	N.A.	Investigative	[27]
VER-54505	DMYD7P5	Solid tumour/cancer	2A00-2F9Z	Investigative	[43]

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

References

• [1] Agreement signed with Prostagenics to develop prostate cancer treatment. Innovate Oncology, Inc. 2005.
• [2] Identification of N,1,4,4-tetramethyl-8-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide (PHA-848125), a potent, orally available cyclin dependent kinase inhibitor. J Med Chem. 2009 Aug 27;52(16):5152-63.
• [3] The cyclin-dependent kinase inhibitor PHA-848125 suppresses the in vitro growth of human melanomas sensitive or resistant to temozolomide, and shows synergistic effects in combination with this triazene compound. Pharmacol Res. 2010 May;61(5):437-48.
• [4] Cell cycle kinases as therapeutic targets for cancer. Nat Rev Drug Discov. 2009 Jul;8(7):547-66.
• [5] 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.
• [6] Cdk2 plays a critical role in hepatocyte cell cycle progression and survival in the setting of cyclin D1 expression in vivo. Cell Cycle. 2009 Sep 1;8(17):2802-9.
• [7] Preclinical metabolism and pharmacokinetics of SB1317 (TG02), a potent CDK/JAK2/FLT3 inhibitor. Drug Metab Lett. 2012 Mar;6(1):33-42.
• [8] Biological characterization of AT7519, a small-molecule inhibitor of cyclin-dependent kinases, in human tumor cell lines. Mol Cancer Ther. 2009 Feb;8(2):324-32.
• [9] AZD5438, an inhibitor of Cdk1, 2, and 9, enhances the radiosensitivity of non-small cell lung carcinoma cells.Int J Radiat Oncol Biol Phys.2012 Nov 15;84(4):e507-14.
• [10] AZD5438, a potent oral inhibitor of cyclin-dependent kinases 1, 2, and 9, leads to pharmacodynamic changes and potent antitumor effects in human tumor xenografts. Mol Cancer Ther. 2009 Jul;8(7):1856-66.
• [11] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [12] Discovery of 4-((7H-Pyrrolo[2,3-d]pyrimidin-4-yl)amino)-N-(4-((4-methylpiperazin-1-yl)methyl)phenyl)-1H-pyrazole-3-carboxamide (FN-1501), an FLT3- and CDK-Kinase Inhibitor with Potentially High Efficiency against Acute Myelocytic Leukemia. J Med Chem. 2018 Feb 22;61(4):1499-1518.
• [13] ClinicalTrials.gov (NCT04553133) PF-07104091 as a Single Agent and in Combination Therapy. U.S. National Institutes of Health.
• [14] 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.
• [15] 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.
• [16] Mechanism of action of SNS-032, a novel cyclin-dependent kinase inhibitor, in chronic lymphocytic leukemia. Blood. 2009 May 7;113(19):4637-45.
• [17] Development of cell-cycle inhibitors for cancer therapy. Curr Oncol. 2009 Mar;16(2):36-43.
• [18] Cyclin-dependent kinase inhibitors for cancer therapy: a patent review (2009 - 2014).Expert Opin Ther Pat. 2015;25(9):953-70.
• [19] c-Jun N-terminal kinase inhibitors: a patent review (2010 - 2014).Expert Opin Ther Pat. 2015;25(8):849-72.
• [20] National Cancer Institute Drug Dictionary (drug id 770319).
• [21] What are next generation innovative therapeutic targets. J Pharmacol Exp Ther. 2009 Jul;330(1):304-15.
• [22] Pharmacological inhibitors of cyclin-dependent kinases. Trends Pharmacol Sci. 2002 Sep;23(9):417-25.
• [23] Pyrido[2,3-d]pyrimidin-7-one inhibitors of cyclin-dependent kinases. J Med Chem. 2000 Nov 30;43(24):4606-16.
• [24] 5,5'-substituted indirubin-3'-oxime derivatives as potent cyclin-dependent kinase inhibitors with anticancer activity. J Med Chem. 2010 May 13;53(9):3696-706.
• [25] How many drug targets are there Nat Rev Drug Discov. 2006 Dec;5(12):993-6.
• [26] 4-arylazo-3,5-diamino-1H-pyrazole CDK inhibitors: SAR study, crystal structure in complex with CDK2, selectivity, and cellular effects. J Med Chem. 2006 Nov 2;49(22):6500-9.
• [27] The Protein Data Bank. Nucleic Acids Res. 2000 Jan 1;28(1):235-42.
• [28] Halogen bonding--a novel interaction for rational drug design J Med Chem. 2009 May 14;52(9):2854-62.
• [29] Design, synthesis, and biological evaluation of 3,4-diarylmaleimides as angiogenesis inhibitors. J Med Chem. 2006 Feb 23;49(4):1271-81.
• [30] DrugBank 3.0: a comprehensive resource for 'omics' research on drugs. Nucleic Acids Res. 2011 Jan;39(Database issue):D1035-41.
• [31] Probing the ATP ribose-binding domain of cyclin-dependent kinases 1 and 2 with O(6)-substituted guanine derivatives. J Med Chem. 2002 Aug 1;45(16):3381-93.
• [32] 4-Alkoxy-2,6-diaminopyrimidine derivatives: inhibitors of cyclin dependent kinases 1 and 2. Bioorg Med Chem Lett. 2003 Jan 20;13(2):217-22.
• [33] Novel structural features of CDK inhibition revealed by an ab initio computational method combined with dynamic simulations. J Med Chem. 2006 Aug 24;49(17):5141-53.
• [34] Identification of binding specificity-determining features in protein families. J Med Chem. 2012 Mar 8;55(5):1926-39.
• [35] 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.
• [36] 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.
• [37] Docking-based development of purine-like inhibitors of cyclin-dependent kinase-2. J Med Chem. 2000 Jun 29;43(13):2506-13.
• [38] 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.
• [39] Discovery of a (1H-benzoimidazol-2-yl)-1H-pyridin-2-one (BMS-536924) inhibitor of insulin-like growth factor I receptor kinase with in vivo antitum... J Med Chem. 2005 Sep 8;48(18):5639-43.
• [40] Novel small molecule inhibitors of 3-phosphoinositide-dependent kinase-1. J Biol Chem. 2005 May 20;280(20):19867-74.
• [41] 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.
• [42] 5-Arylamino-2-methyl-4,7-dioxobenzothiazoles as inhibitors of cyclin-dependent kinase 4 and cytotoxic agents. Bioorg Med Chem Lett. 2000 Mar 6;10(5):461-4.
• [43] 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: 1973).
• [44] Discovery and in vitro evaluation of potent TrkA kinase inhibitors: oxindole and aza-oxindoles. Bioorg Med Chem Lett. 2004 Feb 23;14(4):953-7.
• [45] 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.
• [46] 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.
• [47] Meriolins (3-(pyrimidin-4-yl)-7-azaindoles): synthesis, kinase inhibitory activity, cellular effects, and structure of a CDK2/cyclin A/meriolin com... J Med Chem. 2008 Feb 28;51(4):737-51.
• [48] Aminopyridine-based c-Jun N-terminal kinase inhibitors with cellular activity and minimal cross-kinase activity. J Med Chem. 2006 Jun 15;49(12):3563-80.
• [49] The p16 status of tumor cell lines identifies small molecule inhibitors specific for cyclin-dependent kinase 4. Clin Cancer Res. 1999 Dec;5(12):4279-86.
• [50] Dissecting the determinants of cyclin-dependent kinase 2 and cyclin-dependent kinase 4 inhibitor selectivity. J Med Chem. 2006 Sep 7;49(18):5470-7.
• [51] 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.
• [52] Cellular characterization of a novel focal adhesion kinase inhibitor. J Biol Chem. 2007 May 18;282(20):14845-52.
• [53] Discovery of drug mode of action and drug repositioning from transcriptional responses. Proc Natl Acad Sci U S A. 2010 Aug 17;107(33):14621-6.
• [54] Imidazole pyrimidine amides as potent, orally bioavailable cyclin-dependent kinase inhibitors. Bioorg Med Chem Lett. 2008 Dec 15;18(24):6486-9.
• [55] 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.
• [56] The selectivity of protein kinase inhibitors: a further update. Biochem J. 2007 Dec 15;408(3):297-315.
• [57] N-Phenyl-4-pyrazolo[1,5-b]pyridazin-3-ylpyrimidin-2-amines as potent and selective inhibitors of glycogen synthase kinase 3 with good cellular effi... J Med Chem. 2004 Sep 9;47(19):4716-30.
• [58] Design, synthesis, and biological evaluation of novel pyrimidine derivatives as CDK2 inhibitors. Eur J Med Chem. 2010 Mar;45(3):1158-66.