Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT7EP05T)

• DOT Name: Cyclin-dependent kinase 4 (CDK4)
• Synonyms: EC 2.7.11.22; Cell division protein kinase 4; PSK-J3
• Gene Name: CDK4
• Related Disease:
  Melanoma, cutaneous malignant, susceptibility to, 3
  Malignant pancreatic neoplasm
• UniProt ID: CDK4_HUMAN
• PDB ID: 2W96; 2W99; 2W9F; 2W9Z; 3G33; 5FWK; 5FWL; 5FWM; 5FWP; 6P8E; 6P8F; 6P8G; 6P8H; 7SJ3
• EC Number: 2.7.11.22
• Pfam ID: PF00069
• Sequence:
  MATSRYEPVAEIGVGAYGTVYKARDPHSGHFVALKSVRVPNGGGGGGGLPISTVREVALL
  RRLEAFEHPNVVRLMDVCATSRTDREIKVTLVFEHVDQDLRTYLDKAPPPGLPAETIKDL
  MRQFLRGLDFLHANCIVHRDLKPENILVTSGGTVKLADFGLARIYSYQMALTPVVVTLWY
  RAPEVLLQSTYATPVDMWSVGCIFAEMFRRKPLFCGNSEADQLGKIFDLIGLPPEDDWPR
  DVSLPRGAFPPRGPRPVQSVVPEMEESGAQLLLEMLTFNPHKRISAFRALQHSYLHKDEG
  NPE
• Function: 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. 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.
• KEGG Pathway:
  Endocrine resistance (hsa01522)
  Cell cycle (hsa04110)
  p53 sig.ling pathway (hsa04115)
  PI3K-Akt sig.ling pathway (hsa04151)
  Cellular senescence (hsa04218)
  Tight junction (hsa04530)
  T cell receptor sig.ling pathway (hsa04660)
  AGE-RAGE sig.ling pathway in diabetic complications (hsa04933)
  Cushing syndrome (hsa04934)
  Hepatitis C (hsa05160)
  Measles (hsa05162)
  Human cytomegalovirus infection (hsa05163)
  Influenza A (hsa05164)
  Human papillomavirus infection (hsa05165)
  Human T-cell leukemia virus 1 infection (hsa05166)
  Kaposi sarcoma-associated herpesvirus infection (hsa05167)
  Epstein-Barr virus infection (hsa05169)
  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)
  Breast cancer (hsa05224)
  Hepatocellular carcinoma (hsa05225)
• Reactome Pathway:
  Oxidative Stress Induced Senescence (R-HSA-2559580)
  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)
  Cyclin D associated events in G1 (R-HSA-69231)
  Ubiquitin-dependent degradation of Cyclin D (R-HSA-75815)
  PTK6 Regulates Cell Cycle (R-HSA-8849470)
  Transcriptional regulation by RUNX2 (R-HSA-8878166)
  Meiotic recombination (R-HSA-912446)
  Transcriptional regulation of granulopoiesis (R-HSA-9616222)
  Evasion of Oncogene Induced Senescence Due to Defective p16INK4A binding to CDK4 (R-HSA-9630791)
  Evasion of Oncogene Induced Senescence Due to Defective p16INK4A binding to CDK4 and CDK6 (R-HSA-9630794)
  Evasion of Oxidative Stress Induced Senescence Due to Defective p16INK4A binding to CDK4 (R-HSA-9632697)
  Evasion of Oxidative Stress Induced Senescence Due to Defective p16INK4A binding to CDK4 and CDK6 (R-HSA-9632700)
  Defective binding of RB1 mutants to E2F1,(E2F2, E2F3) (R-HSA-9661069)
  Drug-mediated inhibition of CDK4/CDK6 activity (R-HSA-9754119)
  SCF(Skp2)-mediated degradation of p27/p21 (R-HSA-187577)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Melanoma, cutaneous malignant, susceptibility to, 3	DIST1QCK	Definitive	Autosomal dominant	[1]
Malignant pancreatic neoplasm	DISH4FJX	Moderate	Autosomal dominant	[2]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Palbociclib	DMD7L94	Approved	Cyclin-dependent kinase 4 (CDK4) decreases the response to substance of Palbociclib.	[95]

99 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Cyclin-dependent kinase 4 (CDK4).	[3]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Cyclin-dependent kinase 4 (CDK4).	[4]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Cyclin-dependent kinase 4 (CDK4).	[5]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Cyclin-dependent kinase 4 (CDK4).	[6]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Cyclin-dependent kinase 4 (CDK4).	[7]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Cyclin-dependent kinase 4 (CDK4).	[8]
Arsenic	DMTL2Y1	Approved	Arsenic increases the expression of Cyclin-dependent kinase 4 (CDK4).	[9]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Cyclin-dependent kinase 4 (CDK4).	[10]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Cyclin-dependent kinase 4 (CDK4).	[11]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Cyclin-dependent kinase 4 (CDK4).	[12]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of Cyclin-dependent kinase 4 (CDK4).	[13]
Selenium	DM25CGV	Approved	Selenium decreases the expression of Cyclin-dependent kinase 4 (CDK4).	[14]
Menadione	DMSJDTY	Approved	Menadione decreases the expression of Cyclin-dependent kinase 4 (CDK4).	[15]
Niclosamide	DMJAGXQ	Approved	Niclosamide decreases the expression of Cyclin-dependent kinase 4 (CDK4).	[16]
Cannabidiol	DM0659E	Approved	Cannabidiol decreases the expression of Cyclin-dependent kinase 4 (CDK4).	[17]
Troglitazone	DM3VFPD	Approved	Troglitazone decreases the expression of Cyclin-dependent kinase 4 (CDK4).	[18]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone increases the expression of Cyclin-dependent kinase 4 (CDK4).	[19]
Aspirin	DM672AH	Approved	Aspirin decreases the expression of Cyclin-dependent kinase 4 (CDK4).	[20]
Paclitaxel	DMLB81S	Approved	Paclitaxel decreases the expression of Cyclin-dependent kinase 4 (CDK4).	[21]
Nicotine	DMWX5CO	Approved	Nicotine decreases the expression of Cyclin-dependent kinase 4 (CDK4).	[22]
Indomethacin	DMSC4A7	Approved	Indomethacin decreases the expression of Cyclin-dependent kinase 4 (CDK4).	[23]
Azacitidine	DMTA5OE	Approved	Azacitidine decreases the expression of Cyclin-dependent kinase 4 (CDK4).	[24]
Simvastatin	DM30SGU	Approved	Simvastatin decreases the expression of Cyclin-dependent kinase 4 (CDK4).	[25]
Sulindac	DM2QHZU	Approved	Sulindac decreases the expression of Cyclin-dependent kinase 4 (CDK4).	[26]
Sorafenib	DMS8IFC	Approved	Sorafenib decreases the expression of Cyclin-dependent kinase 4 (CDK4).	[27]
Imatinib	DM7RJXL	Approved	Imatinib decreases the expression of Cyclin-dependent kinase 4 (CDK4).	[28]
Ritonavir	DMU764S	Approved	Ritonavir decreases the expression of Cyclin-dependent kinase 4 (CDK4).	[29]
Melatonin	DMKWFBT	Approved	Melatonin decreases the expression of Cyclin-dependent kinase 4 (CDK4).	[30]
Orlistat	DMRJSP8	Approved	Orlistat decreases the expression of Cyclin-dependent kinase 4 (CDK4).	[31]
Hesperetin	DMKER83	Approved	Hesperetin decreases the expression of Cyclin-dependent kinase 4 (CDK4).	[32]
Clotrimazole	DMMFCIH	Approved	Clotrimazole decreases the expression of Cyclin-dependent kinase 4 (CDK4).	[33]
Thioridazine	DM35M8J	Approved	Thioridazine decreases the expression of Cyclin-dependent kinase 4 (CDK4).	[34]
Clofibrate	DMPC1J7	Approved	Clofibrate decreases the expression of Cyclin-dependent kinase 4 (CDK4).	[35]
Salbutamol	DMN9CWF	Approved	Salbutamol increases the expression of Cyclin-dependent kinase 4 (CDK4).	[36]
Vemurafenib	DM62UG5	Approved	Vemurafenib decreases the expression of Cyclin-dependent kinase 4 (CDK4).	[37]
AC220	DM8Y4JS	Approved	AC220 decreases the expression of Cyclin-dependent kinase 4 (CDK4).	[38]
Dronedarone	DMA8FS5	Approved	Dronedarone decreases the expression of Cyclin-dependent kinase 4 (CDK4).	[39]
Hesperidin	DMI5DW1	Approved	Hesperidin decreases the expression of Cyclin-dependent kinase 4 (CDK4).	[41]
Thiazolidinedione	DMC1NBW	Approved	Thiazolidinedione decreases the expression of Cyclin-dependent kinase 4 (CDK4).	[42]
Memantine	DMD9WSC	Approved	Memantine increases the expression of Cyclin-dependent kinase 4 (CDK4).	[43]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Cyclin-dependent kinase 4 (CDK4).	[44]
Berberine	DMC5Q8X	Phase 4	Berberine decreases the expression of Cyclin-dependent kinase 4 (CDK4).	[45]
Silymarin	DMXBYQR	Phase 4	Silymarin decreases the expression of Cyclin-dependent kinase 4 (CDK4).	[46]
Resveratrol	DM3RWXL	Phase 3	Resveratrol decreases the expression of Cyclin-dependent kinase 4 (CDK4).	[47]
Epigallocatechin gallate	DMCGWBJ	Phase 3	Epigallocatechin gallate decreases the expression of Cyclin-dependent kinase 4 (CDK4).	[48]
Curcumin	DMQPH29	Phase 3	Curcumin decreases the expression of Cyclin-dependent kinase 4 (CDK4).	[49]
HMPL-004	DM29XGY	Phase 3	HMPL-004 decreases the expression of Cyclin-dependent kinase 4 (CDK4).	[50]
I3C	DMIGFOR	Phase 3	I3C decreases the activity of Cyclin-dependent kinase 4 (CDK4).	[51]
Glycyrrhizin	DM8M2N3	Phase 3	Glycyrrhizin decreases the expression of Cyclin-dependent kinase 4 (CDK4).	[52]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the activity of Cyclin-dependent kinase 4 (CDK4).	[53]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Cyclin-dependent kinase 4 (CDK4).	[54]
Belinostat	DM6OC53	Phase 2	Belinostat decreases the expression of Cyclin-dependent kinase 4 (CDK4).	[55]
GSK2110183	DMZHB37	Phase 2	GSK2110183 decreases the expression of Cyclin-dependent kinase 4 (CDK4).	[56]
phorbol 12-myristate 13-acetate	DMJWD62	Phase 2	phorbol 12-myristate 13-acetate decreases the expression of Cyclin-dependent kinase 4 (CDK4).	[57]
Tanespimycin	DMNLQHK	Phase 2	Tanespimycin decreases the expression of Cyclin-dependent kinase 4 (CDK4).	[58]
BAICALEIN	DM4C7E6	Phase 2	BAICALEIN increases the expression of Cyclin-dependent kinase 4 (CDK4).	[59]
Flavopiridol	DMKSUOI	Phase 2	Flavopiridol decreases the activity of Cyclin-dependent kinase 4 (CDK4).	[60]
URSOLIC ACID	DM4SOAW	Phase 2	URSOLIC ACID decreases the expression of Cyclin-dependent kinase 4 (CDK4).	[61]
2-hydroxyoleic acid	DMCLKA4	Phase 1/2	2-hydroxyoleic acid decreases the expression of Cyclin-dependent kinase 4 (CDK4).	[62]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Cyclin-dependent kinase 4 (CDK4).	[63]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Cyclin-dependent kinase 4 (CDK4).	[64]
IRX4204	DM9SCME	Phase 1	IRX4204 decreases the expression of Cyclin-dependent kinase 4 (CDK4).	[65]
AMG 900	DMASGXJ	Phase 1	AMG 900 decreases the expression of Cyclin-dependent kinase 4 (CDK4).	[66]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Cyclin-dependent kinase 4 (CDK4).	[67]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the expression of Cyclin-dependent kinase 4 (CDK4).	[6]
PMID26394986-Compound-22	DM43Z1G	Patented	PMID26394986-Compound-22 decreases the expression of Cyclin-dependent kinase 4 (CDK4).	[68]
PMID25656651-Compound-5	DMAI95U	Patented	PMID25656651-Compound-5 decreases the expression of Cyclin-dependent kinase 4 (CDK4).	[38]
Steroid derivative 1	DMB0NVQ	Patented	Steroid derivative 1 decreases the expression of Cyclin-dependent kinase 4 (CDK4).	[69]
PMID26882240-Compound-32	DMJS4RP	Patented	PMID26882240-Compound-32 decreases the expression of Cyclin-dependent kinase 4 (CDK4).	[12]
Geldanamycin	DMS7TC5	Discontinued in Phase 2	Geldanamycin decreases the expression of Cyclin-dependent kinase 4 (CDK4).	[70]
Dioscin	DM5H2W9	Preclinical	Dioscin decreases the expression of Cyclin-dependent kinase 4 (CDK4).	[71]
Ciglitazone	DMAPO0T	Preclinical	Ciglitazone decreases the expression of Cyclin-dependent kinase 4 (CDK4).	[35]
Piperlongumine	DMIZCOE	Preclinical	Piperlongumine decreases the expression of Cyclin-dependent kinase 4 (CDK4).	[72]
EMODIN	DMAEDQG	Terminated	EMODIN decreases the expression of Cyclin-dependent kinase 4 (CDK4).	[73]
Acteoside	DM0YHKB	Terminated	Acteoside decreases the activity of Cyclin-dependent kinase 4 (CDK4).	[74]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Cyclin-dependent kinase 4 (CDK4).	[8]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Cyclin-dependent kinase 4 (CDK4).	[55]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the expression of Cyclin-dependent kinase 4 (CDK4).	[75]
Deguelin	DMXT7WG	Investigative	Deguelin decreases the expression of Cyclin-dependent kinase 4 (CDK4).	[76]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A decreases the expression of Cyclin-dependent kinase 4 (CDK4).	[77]
methyl p-hydroxybenzoate	DMO58UW	Investigative	methyl p-hydroxybenzoate increases the expression of Cyclin-dependent kinase 4 (CDK4).	[78]
Glyphosate	DM0AFY7	Investigative	Glyphosate decreases the expression of Cyclin-dependent kinase 4 (CDK4).	[79]
geraniol	DMS3CBD	Investigative	geraniol decreases the expression of Cyclin-dependent kinase 4 (CDK4).	[80]
Phencyclidine	DMQBEYX	Investigative	Phencyclidine decreases the expression of Cyclin-dependent kinase 4 (CDK4).	[81]
AHPN	DM8G6O4	Investigative	AHPN decreases the expression of Cyclin-dependent kinase 4 (CDK4).	[82]
Rapamycin Immunosuppressant Drug	DM678IB	Investigative	Rapamycin Immunosuppressant Drug decreases the expression of Cyclin-dependent kinase 4 (CDK4).	[83]
U0126	DM31OGF	Investigative	U0126 decreases the expression of Cyclin-dependent kinase 4 (CDK4).	[84]
Dibutyl phthalate	DMEDGKO	Investigative	Dibutyl phthalate increases the expression of Cyclin-dependent kinase 4 (CDK4).	[85]
Daidzein	DMRFTJX	Investigative	Daidzein decreases the activity of Cyclin-dependent kinase 4 (CDK4).	[53]
2-tert-butylbenzene-1,4-diol	DMNXI1E	Investigative	2-tert-butylbenzene-1,4-diol increases the expression of Cyclin-dependent kinase 4 (CDK4).	[86]
Apicidin	DM83WVF	Investigative	Apicidin decreases the expression of Cyclin-dependent kinase 4 (CDK4).	[87]
Galangin	DM5TQ2O	Investigative	Galangin decreases the expression of Cyclin-dependent kinase 4 (CDK4).	[88]
I-BET151	DMYRUH2	Investigative	I-BET151 decreases the expression of Cyclin-dependent kinase 4 (CDK4).	[89]
gingerol	DMNXYSM	Investigative	gingerol decreases the expression of Cyclin-dependent kinase 4 (CDK4).	[90]
USNIC ACID	DMGOURX	Investigative	USNIC ACID decreases the expression of Cyclin-dependent kinase 4 (CDK4).	[91]
Wogonin	DMGCF51	Investigative	Wogonin decreases the expression of Cyclin-dependent kinase 4 (CDK4).	[92]
Syringic Acid	DM802V7	Investigative	Syringic Acid decreases the expression of Cyclin-dependent kinase 4 (CDK4).	[93]
DEMETHOXYCURCUMIN	DMO5UGV	Investigative	DEMETHOXYCURCUMIN decreases the expression of Cyclin-dependent kinase 4 (CDK4).	[94]
DIECKOL	DMBCK4G	Investigative	DIECKOL decreases the expression of Cyclin-dependent kinase 4 (CDK4).	[21]

1 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Tetracaine	DM9J6C2	Approved	Tetracaine decreases the phosphorylation of Cyclin-dependent kinase 4 (CDK4).	[40]

References

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