Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TT0PG8F)

• DTT Name: Cyclin-dependent kinase 4 (CDK4)
• Synonyms: PSK-J3; Cell division protein kinase 4
• Gene Name: CDK4
• DTT Type: Successful target; [1]
• BioChemical Class: Kinase
• UniProt ID: CDK4_HUMAN
• TTD ID: T85799
• EC Number: EC 2.7.11.22
• Sequence:
  MATSRYEPVAEIGVGAYGTVYKARDPHSGHFVALKSVRVPNGGGGGGGLPISTVREVALL
  RRLEAFEHPNVVRLMDVCATSRTDREIKVTLVFEHVDQDLRTYLDKAPPPGLPAETIKDL
  MRQFLRGLDFLHANCIVHRDLKPENILVTSGGTVKLADFGLARIYSYQMALTPVVVTLWY
  RAPEVLLQSTYATPVDMWSVGCIFAEMFRRKPLFCGNSEADQLGKIFDLIGLPPEDDWPR
  DVSLPRGAFPPRGPRPVQSVVPEMEESGAQLLLEMLTFNPHKRISAFRALQHSYLHKDEG
  NPE
• Function: Phosphorylation of RB1 allows dissociation of the transcription factor E2F from the RB/E2F complexes and the subsequent transcription of E2F target genes which are responsible for the progression through the G(1) phase. Hypophosphorylates RB1 in early G(1) phase. Cyclin D-CDK4 complexes are major integrators of various mitogenenic and antimitogenic signals. Also phosphorylates SMAD3 in a cell-cycle-dependent manner and represses its transcriptional activity. Component of the ternary complex, cyclin D/CDK4/CDKN1B, required for nuclear translocation and activity of the cyclin D-CDK4 complex. Ser/Thr-kinase component of cyclin D-CDK4 (DC) complexes that phosphorylate and inhibit members of the retinoblastoma (RB) protein family including RB1 and regulate the cell-cycle during G(1)/S transition.
• KEGG Pathway:
  Cell cycle (hsa04110)
  p53 signaling pathway (hsa04115)
  PI3K-Akt signaling pathway (hsa04151)
  Tight junction (hsa04530)
  T cell receptor signaling pathway (hsa04660)
  Hepatitis B (hsa05161)
  Measles (hsa05162)
  HTLV-I infection (hsa05166)
  Pathways in cancer (hsa05200)
  Viral carcinogenesis (hsa05203)
  Pancreatic cancer (hsa05212)
  Glioma (hsa05214)
  Melanoma (hsa05218)
  Bladder cancer (hsa05219)
  Chronic myeloid leukemia (hsa05220)
  Small cell lung cancer (hsa05222)
  Non-small cell lung cancer (hsa05223)
• Reactome Pathway:
  Senescence-Associated Secretory Phenotype (SASP) (R-HSA-2559582)
  Oncogene Induced Senescence (R-HSA-2559585)
  RMTs methylate histone arginines (R-HSA-3214858)
  Transcriptional regulation of white adipocyte differentiation (R-HSA-381340)
  Ubiquitin-dependent degradation of Cyclin D1 (R-HSA-69229)
  Cyclin D associated events in G1 (R-HSA-69231)
  Meiotic recombination (R-HSA-912446)
  Oxidative Stress Induced Senescence (R-HSA-2559580)

Molecular Interaction Atlas (MIA) of This DTT

5 Approved Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Apremilast	DMTWS9E	Psoriasis vulgaris	EA90	Approved	[1]
LY2835219	DM93VBZ	Breast cancer	2C60-2C65	Approved	[2]
Palbociclib	DMD7L94	Breast cancer	2C60-2C65	Approved	[3]
Ribociclib Succinate	DM9CIUW	Breast cancer	2C60-2C65	Approved	[4]
Trilaciclib	DMP5A4T	Small-cell lung cancer	2C25.Y	Approved	[5]

16 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
LEE011	DMMX75K	Breast cancer	2C60-2C65	Phase 3	[6]
G1T38	DMQO2IT	Breast cancer	2C60-2C65	Phase 2	[7]
P-276	DMMJUHD	Breast cancer	2C60-2C65	Phase 2	[8]
P276-00	DM9DJL2	Mantle cell lymphoma	2A85.5	Phase 2	[9]
Ro 31-7453	DM83QCL	Solid tumour/cancer	2A00-2F9Z	Phase 2	[10]
FCN-437	DMQ8VUW	Breast cancer	2C60-2C65	Phase 1/2	[11]
GLR2007	DM7DWLY	Glioblastoma of brain	2A00.00	Phase 1/2	[12]
NUV-422	DMQJQNT	Malignant glioma	2A00.0	Phase 1/2	[13]
AG-024322	DMY4WVK	Solid tumour/cancer	2A00-2F9Z	Phase 1	[9]
FN-1501	DM7BMD6	Solid tumour/cancer	2A00-2F9Z	Phase 1	[14]
G1T28-1	DML028U	Solid tumour/cancer	2A00-2F9Z	Phase 1	[2]
P1446A-05	DMXHKYJ	Solid tumour/cancer	2A00-2F9Z	Phase 1	[9]
PF-07220060	DMPKO84	Liposarcoma	2B59	Phase 1	[15]
PHA-793887	DM2Y4FG	Solid tumour/cancer	2A00-2F9Z	Phase 1	[8]
RGB-286638	DMEGOQP	Haematological malignancy	2B33.Y	Phase 1	[8]
RGT-419B	DMD2MND	Breast cancer	2C60-2C65	Phase 1	[16]

13 Patented Agent(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Imidazo pyridine derivative 3	DMPCLZB	N. A.	N. A.	Patented	[17]
Indole-based analog 13	DMV7DFM	N. A.	N. A.	Patented	[17]
Isoquinoline 1,3-dione derivative 1	DMIYUAN	N. A.	N. A.	Patented	[17]
Oxazolyl methylthiothiazole derivative 1	DMZM6FW	N. A.	N. A.	Patented	[17]
PMID25726713-Compound-47	DMXE5KM	N. A.	N. A.	Patented	[18]
PMID25726713-Compound-48	DMSIOUA	N. A.	N. A.	Patented	[18]
PMID25726713-Compound-49	DM2CT4G	N. A.	N. A.	Patented	[18]
PMID25726713-Compound-50	DM3BDFV	N. A.	N. A.	Patented	[18]
PMID25726713-Compound-51	DMF0OW4	N. A.	N. A.	Patented	[18]
PMID25991433-Compound-A1	DM89LF0	N. A.	N. A.	Patented	[19]
PMID26161698-Compound-17	DMB92RA	N. A.	N. A.	Patented	[17]
Pyrrolo[2,3-d]pyrimidine derivative 10	DMRWG2E	N. A.	N. A.	Patented	[17]
Pyrrolo[2,3-d]pyrimidine derivative 9	DM0HU5O	N. A.	N. A.	Patented	[17]

5 Discontinued Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
BAY 10-00394	DMV2DIW	Small-cell lung cancer	2C25.Y	Discontinued in Phase 2	[8]
R547	DMK25FU	Advanced solid tumour	2A00-2F9Z	Discontinued in Phase 1	[9]
ZK 304709	DMJ9R4A	Advanced solid tumour	2A00-2F9Z	Discontinued in Phase 1	[9]
CYC-103	DM17NYA	Solid tumour/cancer	2A00-2F9Z	Terminated	[8]
PD-0183812	DMWYP86	Retinoblastoma	2D02.2	Terminated	[20]

1 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	[8]

21 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
1-(1H-Indazol-6-yl)-3-pyridin-2-yl-urea	DM9MCAU	Discovery agent	N.A.	Investigative	[21]
1-(7-Hydroxy-naphthalen-1-yl)-3-pyridin-2-yl-urea	DM7OGLI	Discovery agent	N.A.	Investigative	[21]
1-(9-Oxo-9H-fluoren-4-yl)-3-pyridin-2-yl-urea	DM30FNL	Discovery agent	N.A.	Investigative	[21]
1-Pyridin-2-yl-3-quinolin-5-yl-urea	DMTMXN4	Discovery agent	N.A.	Investigative	[21]
10-hydroxy-18-methoxybetaenone	DM4R7X8	Discovery agent	N.A.	Investigative	[22]
3,4-di-(4-methoxyphenyl)-1H-pyrrole-2,5-dione	DMDO175	Discovery agent	N.A.	Investigative	[23]
3,4-diphenyl-1H-pyrrole-2,5-dione	DMPK6YT	Discovery agent	N.A.	Investigative	[23]
3-(4-methoxyphenyl)-4-phenyl-1H-pyrrole-2,5-dione	DMGC7RY	Discovery agent	N.A.	Investigative	[23]
3-(indole-3-yl)-4-phenyl-1H-pyrrole-2,5-dione	DM3EV9N	Discovery agent	N.A.	Investigative	[23]
4-[(3,5-diamino-1H-pyrazol-4-yl)diazenyl]phenol	DMSKJ1X	Discovery agent	N.A.	Investigative	[24]
Cdk4 inhibitor III	DMNZJAX	Discovery agent	N.A.	Investigative	[25]
Fascaplysin	DMG5OZP	Discovery agent	N.A.	Investigative	[20]
K00024	DMP8M9Q	Discovery agent	N.A.	Investigative	[26]
N-(2-(1H-Indol-3-yl)ethyl)biphenyl-4-carboxamide	DM6NC8G	Discovery agent	N.A.	Investigative	[27]
NSC-625987	DMLG05U	Discovery agent	N.A.	Investigative	[28]
NU-6102	DMMOFKD	Discovery agent	N.A.	Investigative	[29]
NU6140	DMCUSG3	Discovery agent	N.A.	Investigative	[30]
PMID18986805C9b	DMFU6AI	Discovery agent	N.A.	Investigative	[31]
PYRAZOLOPYRIDAZINE 1	DMKTB5U	Discovery agent	N.A.	Investigative	[32]
PYRAZOLOPYRIDAZINE 2	DMI7AUJ	Discovery agent	N.A.	Investigative	[32]
Ro-0505124	DMLVERQ	Discovery agent	N.A.	Investigative	[33]

Molecular Expression Atlas (MEA) of This DTT

Disease Name	ICD 11	Studied Tissue	p-value	Fold-Change	Z-score
Lung cancer	2C82	Lung tissue	3.30E-72	0.65	2.39
Breast cancer	2C82	Breast tissue	1.29E-37	0.42	1.08
Psoriasis	EA90	Skin	1.06E-02	-0.1	-0.44

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