Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTL4Q97)

• DTT Name: Cyclin-dependent kinase 5 (CDK5)
• Synonyms: Tau protein kinase II catalytic subunit; TPKII catalytic subunit; Serine/threonine-protein kinase PSSALRE; Serine/threonine protein kinase PSSALRE; Proline-directed protein kinase F(A) (PDPK F(A)); Proline-directed protein kinase 33 kDa subunit; PDPK; Cyclin-dependent-like kinase 5; Cyclin-dependent kinase 5 (CDK5); Cell division protein kinase 5; CDKN5
• Gene Name: CDK5
• DTT Type: Patented-recorded target; [1]
• BioChemical Class: Kinase
• UniProt ID: CDK5_HUMAN
• TTD ID: T20973
• EC Number: EC 2.7.11.1
• Sequence:
  MQKYEKLEKIGEGTYGTVFKAKNRETHEIVALKRVRLDDDDEGVPSSALREICLLKELKH
  KNIVRLHDVLHSDKKLTLVFEFCDQDLKKYFDSCNGDLDPEIVKSFLFQLLKGLGFCHSR
  NVLHRDLKPQNLLINRNGELKLADFGLARAFGIPVRCYSAEVVTLWYRPPDVLFGAKLYS
  TSIDMWSAGCIFAELANAGRPLFPGNDVDDQLKRIFRLLGTPTEEQWPSMTKLPDYKPYP
  MYPATTSLVNVVPKLNATGRDLLQNLLKCNPVQRISAEEALQHPYFSDFCPP
• Function: Interacts with D1 and D3-type G1 cyclins. Phosphorylates SRC, NOS3, VIM/vimentin, p35/CDK5R1, MEF2A, SIPA1L1, SH3GLB1, PXN, PAK1, MCAM/MUC18, SEPT5, SYN1, DNM1, AMPH, SYNJ1, CDK16, RAC1, RHOA, CDC42, TONEBP/NFAT5, MAPT/TAU, MAP1B, histone H1, p53/TP53, HDAC1, APEX1, PTK2/FAK1, huntingtin/HTT, ATM, MAP2, NEFH and NEFM. Regulates several neuronal development and physiological processes including neuronal survival, migration and differentiation, axonal and neurite growth, synaptogenesis, oligodendrocyte differentiation, synaptic plasticity and neurotransmission, by phosphorylating key proteins. Activated by interaction with CDK5R1 (p35) and CDK5R2 (p39), especially in post-mitotic neurons, and promotes CDK5R1 (p35) expression in an autostimulation loop. Phosphorylates many downstream substrates such as Rho and Ras family small GTPases (e. g. PAK1, RAC1, RHOA, CDC42) or microtubule-binding proteins (e. g. MAPT/TAU, MAP2, MAP1B), and modulates actin dynamics to regulate neurite growth and/or spine morphogenesis. Phosphorylates also exocytosis associated proteins such as MCAM/MUC18, SEPT5, SYN1, and CDK16/PCTAIRE1 as well as endocytosis associated proteins such as DNM1, AMPH and SYNJ1 at synaptic terminals. In the mature central nervous system (CNS), regulates neurotransmitter movements by phosphorylating substrates associated with neurotransmitter release and synapse plasticity; synaptic vesicle exocytosis, vesicles fusion with the presynaptic membrane, and endocytosis. Promotes cell survival by activating anti-apoptotic proteins BCL2 and STAT3, and negatively regulating of JNK3/MAPK10 activity. Phosphorylation of p53/TP53 in response to genotoxic and oxidative stresses enhances its stabilization by preventing ubiquitin ligase-mediated proteasomal degradation, and induces transactivation of p53/TP53 target genes, thus regulating apoptosis. Phosphorylation of p35/CDK5R1 enhances its stabilization by preventing calpain-mediated proteolysis producing p25/CDK5R1 and avoiding ubiquitin ligase-mediated proteasomal degradation. During aberrant cell-cycle activity and DNA damage, p25/CDK5 activity elicits cell-cycle activity and double-strand DNA breaks that precedes neuronal death by deregulating HDAC1. DNA damage triggered phosphorylation of huntingtin/HTT in nuclei of neurons protects neurons against polyglutamine expansion as well as DNA damage mediated toxicity. Phosphorylation of PXN reduces its interaction with PTK2/FAK1 in matrix-cell focal adhesions (MCFA) during oligodendrocytes (OLs) differentiation. Negative regulator of Wnt/beta-catenin signaling pathway. Activator of the GAIT (IFN-gamma-activated inhibitor of translation) pathway, which suppresses expression of a post-transcriptional regulon of proinflammatory genes in myeloid cells; phosphorylates the linker domain of glutamyl-prolyl tRNA synthetase (EPRS) in a IFN-gamma-dependent manner, the initial event in assembly of the GAIT complex. Phosphorylation of SH3GLB1 is required for autophagy induction in starved neurons. Phosphorylation of TONEBP/NFAT5 in response to osmotic stress mediates its rapid nuclear localization. MEF2 is inactivated by phosphorylation in nucleus in response to neurotoxin, thus leading to neuronal apoptosis. APEX1 AP-endodeoxyribonuclease is repressed by phosphorylation, resulting in accumulation of DNA damage and contributing to neuronal death. NOS3 phosphorylation down regulates NOS3-derived nitrite (NO) levels. SRC phosphorylation mediates its ubiquitin-dependent degradation and thus leads to cytoskeletal reorganization. May regulate endothelial cell migration and angiogenesis via the modulation of lamellipodia formation. Involved in dendritic spine morphogenesis by mediating the EFNA1-EPHA4 signaling. The complex p35/CDK5 participates in the regulation of the circadian clock by modulating the function of CLOCK protein: phosphorylates CLOCK at 'Thr-451' and 'Thr-461' and regulates the transcriptional activity of the CLOCK-ARNTL/BMAL1 heterodimer in association with altered stability and subcellular distribution. Proline-directed serine/threonine-protein kinase essential for neuronal cell cycle arrest and differentiation and may be involved in apoptotic cell death in neuronal diseases by triggering abortive cell cycle re-entry.
• KEGG Pathway:
  Axon guidance (hsa04360)
  Alzheimer's disease (hsa05010)
  Cocaine addiction (hsa05030)
• Reactome Pathway:
  CRMPs in Sema3A signaling (R-HSA-399956)
  Factors involved in megakaryocyte development and platelet production (R-HSA-983231)
  DARPP-32 events (R-HSA-180024)

Molecular Interaction Atlas (MIA) of This DTT

8 Patented Agent(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
4-(thiazol-5-yl)-pyrimidine derivative 2	DMMQFCN	N. A.	N. A.	Patented	[2]
Flavonoid derivative 7	DM6A9UR	N. A.	N. A.	Patented	[2]
KENPAULLONE	DMAGVXW	Discovery agent	N.A.	Patented	[1]
Naphthyridine and isoquinoline derivative 1	DMTGIP7	N. A.	N. A.	Patented	[2]
PMID26161698-Compound-18	DM6JVR5	N. A.	N. A.	Patented	[2]
Pyrazolo[1,5-a]-1,3,5-triazine derivative 1	DMOK7CW	N. A.	N. A.	Patented	[2]
Roscovitine derivative 1	DMD1G3Z	N. A.	N. A.	Patented	[2]
Tricyclic benzimidazole derivative 1	DM5SD9E	N. A.	N. A.	Patented	[2]

1 Preclinical Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
L-751250	DMOERXK	Obesity	5B81	Preclinical	[3]

1 Discontinued Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Olomoucine	DMNAFG1	N. A.	N. A.	Terminated	[3]

16 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
1-phenyl-3-(2-(pyridin-4-yl)thiazol-4-yl)urea	DMJVITG	Discovery agent	N.A.	Investigative	[4]
10Z-Hymenialdisine	DMIRSA5	Discovery agent	N.A.	Investigative	[3]
3-(2-phenylthiazol-4-yl)quinolin-2(1H)-one	DMQC9WV	Discovery agent	N.A.	Investigative	[5]
9-Nitropaullone	DM8LUYM	Discovery agent	N.A.	Investigative	[3]
aloisine A	DM5U1LN	Discovery agent	N.A.	Investigative	[6]
aminopurvalanol A	DMKLC3O	N. A.	N. A.	Investigative	[7]
AZAKENPAULLONE	DM61H07	Discovery agent	N.A.	Investigative	[1]
Indirubin-3'-monoxime	DMLRQH0	Discovery agent	N.A.	Investigative	[3]
Indirubin-5-sulfonate	DM08VHZ	Discovery agent	N.A.	Investigative	[3]
MANZAMINE A	DMB3GNC	Discovery agent	N.A.	Investigative	[8]
NU6140	DMCUSG3	Discovery agent	N.A.	Investigative	[9]
Oxindole 16 (compound 3)	DMM5208	Discovery agent	N.A.	Investigative	[3]
Oxindole 95	DM4UL1G	Discovery agent	N.A.	Investigative	[3]
Quinoxaline1	DMRWXH4	Discovery agent	N.A.	Investigative	[7]
SU9516	DMQHG0R	Discovery agent	N.A.	Investigative	[3]
Thieno analogue of kenpaullone	DMIOTHG	Discovery agent	N.A.	Investigative	[1]

References

• [1] 1-Azakenpaullone is a selective inhibitor of glycogen synthase kinase-3 beta. Bioorg Med Chem Lett. 2004 Jan 19;14(2):413-6.
• [2] Cyclin-dependent kinase inhibitors for cancer therapy: a patent review (2009 - 2014).Expert Opin Ther Pat. 2015;25(9):953-70.
• [3] Pharmacological inhibitors of cyclin-dependent kinases. Trends Pharmacol Sci. 2002 Sep;23(9):417-25.
• [4] Structure-activity relationships of 3,4-dihydro-1H-quinazolin-2-one derivatives as potential CDK5 inhibitors. Bioorg Med Chem. 2007 Oct 15;15(20):6574-95.
• [5] Design and synthesis of quinolin-2(1H)-one derivatives as potent CDK5 inhibitors. Bioorg Med Chem Lett. 2007 Oct 1;17(19):5384-9.
• [6] 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.
• [7] 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.
• [8] Glycogen synthase kinase-3 (GSK-3) inhibitory activity and structure-activity relationship (SAR) studies of the manzamine alkaloids. Potential for ... J Nat Prod. 2007 Sep;70(9):1397-405.
• [9] 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.