Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTO0FDJ)

• DTT Name: Cyclin-dependent kinase 6 (CDK6)
• Synonyms: Serine/threonine-protein kinase PLSTIRE; Serine/threonine protein kinase PLSTIRE; Cell division protein kinase 6; CDKN6
• Gene Name: CDK6
• DTT Type: Successful target; [1]
• BioChemical Class: Kinase
• UniProt ID: CDK6_HUMAN
• TTD ID: T89361
• EC Number: EC 2.7.11.22
• Sequence:
  MEKDGLCRADQQYECVAEIGEGAYGKVFKARDLKNGGRFVALKRVRVQTGEEGMPLSTIR
  EVAVLRHLETFEHPNVVRLFDVCTVSRTDRETKLTLVFEHVDQDLTTYLDKVPEPGVPTE
  TIKDMMFQLLRGLDFLHSHRVVHRDLKPQNILVTSSGQIKLADFGLARIYSFQMALTSVV
  VTLWYRAPEVLLQSSYATPVDLWSVGCIFAEMFRRKPLFRGSSDVDQLGKILDVIGLPGE
  EDWPRDVALPRQAFHSKSAQPIEKFVTDIDELGKDLLLKCLTFNPAKRISAYSALSHPYF
  QDLERCKENLDSHLPPSQNTSELNTA
• Function: Phosphorylates pRB/RB1 and NPM1. Interacts with D-type G1 cyclins during interphase at G1 to form a pRB/RB1 kinase and controls the entrance into the cell cycle. Involved in initiation and maintenance of cell cycle exit during cell differentiation; prevents cell proliferation and regulates negatively cell differentiation, but is required for the proliferation of specific cell types (e. g. erythroid and hematopoietic cells). Essential for cell proliferation within the dentate gyrus of the hippocampus and the subventricular zone of the lateral ventricles. Required during thymocyte development. Promotes the production of newborn neurons, probably by modulating G1 length. Promotes, at least in astrocytes, changes in patterns of gene expression, changes in the actin cytoskeleton including loss of stress fibers, and enhanced motility during cell differentiation. Prevents myeloid differentiation by interfering with RUNX1 and reducing its transcription transactivation activity, but promotes proliferation of normal myeloid progenitors. Delays senescence. Promotes the proliferation of beta-cells in pancreatic islets of Langerhans. May play a role in the centrosome organization during the cell cycle phases. Serine/threonine-protein kinase involved in the control of the cell cycle and differentiation; promotes G1/S transition.
• KEGG Pathway:
  Cell cycle (hsa04110)
  p53 signaling pathway (hsa04115)
  PI3K-Akt signaling pathway (hsa04151)
  Hepatitis B (hsa05161)
  Measles (hsa05162)
  Pathways in cancer (hsa05200)
  Viral carcinogenesis (hsa05203)
  MicroRNAs in cancer (hsa05206)
  Pancreatic cancer (hsa05212)
  Glioma (hsa05214)
  Melanoma (hsa05218)
  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)
  Cyclin D associated events in G1 (R-HSA-69231)
  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]

8 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]
FCN-437	DMQ8VUW	Breast cancer	2C60-2C65	Phase 1/2	[8]
GLR2007	DM7DWLY	Glioblastoma of brain	2A00.00	Phase 1/2	[9]
NUV-422	DMQJQNT	Malignant glioma	2A00.0	Phase 1/2	[10]
FN-1501	DM7BMD6	Solid tumour/cancer	2A00-2F9Z	Phase 1	[11]
G1T28-1	DML028U	Solid tumour/cancer	2A00-2F9Z	Phase 1	[2]
RGT-419B	DMD2MND	Breast cancer	2C60-2C65	Phase 1	[12]

7 Patented Agent(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Isoquinoline 1,3-dione derivative 1	DMIYUAN	N. A.	N. A.	Patented	[13]
Oxazolyl methylthiothiazole derivative 1	DMZM6FW	N. A.	N. A.	Patented	[13]
PMID25726713-Compound-47	DMXE5KM	N. A.	N. A.	Patented	[14]
PMID25726713-Compound-48	DMSIOUA	N. A.	N. A.	Patented	[14]
PMID25726713-Compound-49	DM2CT4G	N. A.	N. A.	Patented	[14]
PMID25726713-Compound-50	DM3BDFV	N. A.	N. A.	Patented	[14]
PMID25726713-Compound-51	DMF0OW4	N. A.	N. A.	Patented	[14]

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	[15]

2 Discontinued Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
CYC-103	DM17NYA	Solid tumour/cancer	2A00-2F9Z	Terminated	[16]
PD-0183812	DMWYP86	Retinoblastoma	2D02.2	Terminated	[17]

9 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
3,4-di-(4-methoxyphenyl)-1H-pyrrole-2,5-dione	DMDO175	Discovery agent	N.A.	Investigative	[18]
3,4-diphenyl-1H-pyrrole-2,5-dione	DMPK6YT	Discovery agent	N.A.	Investigative	[18]
3,7,3',4'-TETRAHYDROXYFLAVONE	DMES906	Discovery agent	N.A.	Investigative	[19]
3-(4-methoxyphenyl)-4-phenyl-1H-pyrrole-2,5-dione	DMGC7RY	Discovery agent	N.A.	Investigative	[18]
APIGENIN	DMI3491	Discovery agent	N.A.	Investigative	[20]
Chrysin	DM7V2LG	Discovery agent	N.A.	Investigative	[20]
Deschloroflavopiridol	DMQER8D	Discovery agent	N.A.	Investigative	[17]
Fascaplysin	DMG5OZP	Discovery agent	N.A.	Investigative	[17]
RGB-286147	DMP08BY	Discovery agent	N.A.	Investigative	[21]

Molecular Expression Atlas (MEA) of This DTT

Disease Name	ICD 11	Studied Tissue	p-value	Fold-Change	Z-score
Psoriasis	EA90	Skin	1.12E-14	-0.67	-1.3

References

• [1] Agreement signed with Prostagenics to develop prostate cancer treatment. Innovate Oncology, Inc. 2005.
• [2] Interpreting expression profiles of cancers by genome-wide survey of breadth of expression in normal tissues. Genomics 2005 Aug;86(2):127-41.
• [3] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health Human Services. 2017
• [4] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services.
• [5] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health Human Services. 2021
• [6] Dual CDK4/CDK6 inhibition induces cell-cycle arrest and senescence in neuroblastoma. Clin Cancer Res. 2013 Nov 15;19(22):6173-82.
• [7] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [8] Clinical pipeline report, company report or official report of Fochon Pharmaceuticals.
• [9] Clinical pipeline report, company report or official report of Gan & Lee Pharmaceuticals.
• [10] ClinicalTrials.gov (NCT04541225) Phase 1/2 Dose Escalation, Safety, Pharmacokinetics, and Efficacy Study of NUV-422 in Adults With Recurrent or Refractory High-grade Gliomas and Solid Tumors. U.S.National Institutes of Health.
• [11] 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.
• [12] Clinical pipeline report, company report or official report of Regor Therapeutics
• [13] Cyclin-dependent kinase inhibitors for cancer therapy: a patent review (2009 - 2014).Expert Opin Ther Pat. 2015;25(9):953-70.
• [14] Hedgehog inhibitors: a patent review (2013 - present).Expert Opin Ther Pat. 2015 May;25(5):549-65.
• [15] What are next generation innovative therapeutic targets. J Pharmacol Exp Ther. 2009 Jul;330(1):304-15.
• [16] WO patent application no. 2007,0898,78, Sutures and anti-scarring agents.
• [17] Pharmacological inhibitors of cyclin-dependent kinases. Trends Pharmacol Sci. 2002 Sep;23(9):417-25.
• [18] Design, synthesis, and biological evaluation of 3,4-diarylmaleimides as angiogenesis inhibitors. J Med Chem. 2006 Feb 23;49(4):1271-81.
• [19] The Protein Data Bank. Nucleic Acids Res. 2000 Jan 1;28(1):235-42.
• [20] Crystal structure of a human cyclin-dependent kinase 6 complex with a flavonol inhibitor, fisetin. J Med Chem. 2005 Feb 10;48(3):737-43.
• [21] 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.