Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TT5U49F)

• DTT Name: PRKACA messenger RNA (PRKACA mRNA)
• Synonyms: cAMP-dependent protein kinase catalytic subunit alpha (mRNA); PKACA (mRNA); PKA C-alpha (mRNA)
• Gene Name: PRKACA
• DTT Type: Patented-recorded target; [1]
• BioChemical Class: mRNA target
• UniProt ID: KAPCA_HUMAN
• TTD ID: T20669
• EC Number: EC 2.7.11.11
• Sequence:
  MGNAAAAKKGSEQESVKEFLAKAKEDFLKKWESPAQNTAHLDQFERIKTLGTGSFGRVML
  VKHKETGNHYAMKILDKQKVVKLKQIEHTLNEKRILQAVNFPFLVKLEFSFKDNSNLYMV
  MEYVPGGEMFSHLRRIGRFSEPHARFYAAQIVLTFEYLHSLDLIYRDLKPENLLIDQQGY
  IQVTDFGFAKRVKGRTWTLCGTPEYLAPEIILSKGYNKAVDWWALGVLIYEMAAGYPPFF
  ADQPIQIYEKIVSGKVRFPSHFSSDLKDLLRNLLQVDLTKRFGNLKNGVNDIKNHKWFAT
  TDWIAIYQRKVEAPFIPKFKGPGDTSNFDDYEEEEIRVSINEKCGKEFSEF
• Function: Regulates the abundance of compartmentalized pools of its regulatory subunits through phosphorylation of PJA2 which binds and ubiquitinates these subunits, leading to their subsequent proteolysis. Phosphorylates CDC25B, ABL1, NFKB1, CLDN3, PSMC5/RPT6, PJA2, RYR2, RORA and VASP. RORA is activated by phosphorylation. Required for glucose-mediated adipogenic differentiation increase and osteogenic differentiation inhibition from osteoblasts. Involved in the regulation of platelets in response to thrombin and collagen; maintains circulating platelets in a resting state by phosphorylating proteins in numerous platelet inhibitory pathways when in complex with NF-kappa-B (NFKB1 and NFKB2) and I-kappa-B-alpha (NFKBIA), but thrombin and collagen disrupt these complexes and free active PRKACA stimulates platelets and leads to platelet aggregation by phosphorylating VASP. Prevents the antiproliferative and anti-invasive effects of alpha-difluoromethylornithine in breast cancer cells when activated. RYR2 channel activity is potentiated by phosphorylation in presence of luminal Ca(2+), leading to reduced amplitude and increased frequency of store overload-induced Ca(2+) release (SOICR) characterized by an increased rate of Ca(2+) release and propagation velocity of spontaneous Ca(2+) waves, despite reduced wave amplitude and resting cytosolic Ca(2+). PSMC5/RPT6 activation by phosphorylation stimulates proteasome. Negatively regulates tight junctions (TJs) in ovarian cancer cells via CLDN3 phosphorylation. NFKB1 phosphorylation promotes NF-kappa-B p50-p50 DNA binding. Involved in embryonic development by down-regulating the Hedgehog (Hh) signaling pathway that determines embryo pattern formation and morphogenesis. Prevents meiosis resumption in prophase-arrested oocytes via CDC25B inactivation by phosphorylation. May also regulate rapid eye movement (REM) sleep in the pedunculopontine tegmental (PPT). Phosphorylates APOBEC3G and AICDA. Isoform 2 phosphorylates and activates ABL1 in sperm flagellum to promote spermatozoa capacitation. Phosphorylates HSF1; this phosphorylation promotes HSF1 nuclear localization and transcriptional activity upon heat shock. Phosphorylates a large number of substrates in the cytoplasm and the nucleus.
• KEGG Pathway:
  MAPK signaling pathway (hsa04010)
  Ras signaling pathway (hsa04014)
  Calcium signaling pathway (hsa04020)
  cAMP signaling pathway (hsa04024)
  Chemokine signaling pathway (hsa04062)
  Oocyte meiosis (hsa04114)
  Apoptosis (hsa04210)
  Adrenergic signaling in cardiomyocytes (hsa04261)
  Vascular smooth muscle contraction (hsa04270)
  Wnt signaling pathway (hsa04310)
  Hedgehog signaling pathway (hsa04340)
  Gap junction (hsa04540)
  Platelet activation (hsa04611)
  Circadian entrainment (hsa04713)
  Long-term potentiation (hsa04720)
  Retrograde endocannabinoid signaling (hsa04723)
  Glutamatergic synapse (hsa04724)
  Cholinergic synapse (hsa04725)
  Serotonergic synapse (hsa04726)
  GABAergic synapse (hsa04727)
  Dopaminergic synapse (hsa04728)
  Olfactory transduction (hsa04740)
  Taste transduction (hsa04742)
  Inflammatory mediator regulation of TRP channels (hsa04750)
  Insulin signaling pathway (hsa04910)
  Insulin secretion (hsa04911)
  GnRH signaling pathway (hsa04912)
  Ovarian steroidogenesis (hsa04913)
  Progesterone-mediated oocyte maturation (hsa04914)
  Estrogen signaling pathway (hsa04915)
  Melanogenesis (hsa04916)
  Thyroid hormone synthesis (hsa04918)
  Thyroid hormone signaling pathway (hsa04919)
  Oxytocin signaling pathway (hsa04921)
  Glucagon signaling pathway (hsa04922)
  Regulation of lipolysis in adipocytes (hsa04923)
  Renin secretion (hsa04924)
  Endocrine and other factor-regulated calcium reabsorption (hsa04961)
  Vasopressin-regulated water reabsorption (hsa04962)
  Salivary secretion (hsa04970)
  Gastric acid secretion (hsa04971)
  Bile secretion (hsa04976)
  Parkinson's disease (hsa05012)
  Prion diseases (hsa05020)
  Cocaine addiction (hsa05030)
  Amphetamine addiction (hsa05031)
  Morphine addiction (hsa05032)
  Alcoholism (hsa05034)
  Vibrio cholerae infection (hsa05110)
  Amoebiasis (hsa05146)
  HTLV-I infection (hsa05166)
  Epstein-Barr virus infection (hsa05169)
  Pathways in cancer (hsa05200)
  Viral carcinogenesis (hsa05203)
  Proteoglycans in cancer (hsa05205)
  Dilated cardiomyopathy (hsa05414)
• Reactome Pathway:
  PKA activation (R-HSA-163615)
  PKA activation in glucagon signalling (R-HSA-164378)
  DARPP-32 events (R-HSA-180024)
  Regulation of PLK1 Activity at G2/M Transition (R-HSA-2565942)
  Loss of Nlp from mitotic centrosomes (R-HSA-380259)
  Recruitment of mitotic centrosome proteins and complexes (R-HSA-380270)
  Loss of proteins required for interphase microtubule organization?from the centrosome (R-HSA-380284)
  Glucagon-like Peptide-1 (GLP1) regulates insulin secretion (R-HSA-381676)
  Regulation of insulin secretion (R-HSA-422356)
  Vasopressin regulates renal water homeostasis via Aquaporins (R-HSA-432040)
  VEGFA-VEGFR2 Pathway (R-HSA-4420097)
  Interleukin-3, 5 and GM-CSF signaling (R-HSA-512988)
  Degradation of GLI1 by the proteasome (R-HSA-5610780)
  Degradation of GLI2 by the proteasome (R-HSA-5610783)
  Hedgehog 'off' state (R-HSA-5610787)
  Anchoring of the basal body to the plasma membrane (R-HSA-5620912)
  CD209 (DC-SIGN) signaling (R-HSA-5621575)
  MAPK6/MAPK4 signaling (R-HSA-5687128)
  Gluconeogenesis (R-HSA-70263)
  Factors involved in megakaryocyte development and platelet production (R-HSA-983231)
  Hormone-sensitive lipase (HSL)-mediated triacylglycerol hydrolysis (R-HSA-163560)

Molecular Interaction Atlas (MIA) of This DTT

3 Patented Agent(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
AGGGWZCOULSEER-PYUWXLGESA-N	DM2L83Y	N. A.	N. A.	Patented	[2]
VFEDEOUBYBLDKN-AAFJCEBUSA-N	DMH9ION	N. A.	N. A.	Patented	[2]
XHPNYYOUZWOWNT-PYUWXLGESA-N	DM5Q93Y	N. A.	N. A.	Patented	[2]

1 Discontinued Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
BALANOL	DMDLN9E	N. A.	N. A.	Terminated	[1]

28 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
4-[(3,5-diamino-1H-pyrazol-4-yl)diazenyl]phenol	DMSKJ1X	Discovery agent	N.A.	Investigative	[3]
H-89	DM4RVGO	Discovery agent	N.A.	Investigative	[4]
ISIS 102450	DML40N3	Discovery agent	N.A.	Investigative	[5]
ISIS 102454	DMNSEH1	Discovery agent	N.A.	Investigative	[5]
ISIS 102458	DMBUTFN	Discovery agent	N.A.	Investigative	[5]
ISIS 102462	DMXNC0B	Discovery agent	N.A.	Investigative	[5]
ISIS 102466	DMAG8QO	Discovery agent	N.A.	Investigative	[5]
ISIS 102478	DMU70ND	Discovery agent	N.A.	Investigative	[5]
ISIS 102482	DMMBJWK	Discovery agent	N.A.	Investigative	[5]
ISIS 102486	DMTMBEX	Discovery agent	N.A.	Investigative	[5]
ISIS 102490	DMMWVCH	Discovery agent	N.A.	Investigative	[5]
ISIS 102558	DMYJO7T	Discovery agent	N.A.	Investigative	[5]
ISIS 102563	DMTHMF0	Discovery agent	N.A.	Investigative	[5]
ISIS 102584	DMEDFLA	Discovery agent	N.A.	Investigative	[5]
ISIS 102599	DM3RVUY	Discovery agent	N.A.	Investigative	[5]
ISIS 102604	DMZ6X9B	Discovery agent	N.A.	Investigative	[5]
ISIS 102609	DM60LT9	Discovery agent	N.A.	Investigative	[5]
ISIS 102614	DMEB36I	Discovery agent	N.A.	Investigative	[5]
ISIS 102619	DMXH9IT	Discovery agent	N.A.	Investigative	[5]
ISIS 102624	DMGO4TZ	Discovery agent	N.A.	Investigative	[5]
ISIS 102629	DMNSZPX	Discovery agent	N.A.	Investigative	[5]
ISIS 102633	DMWT7BK	Discovery agent	N.A.	Investigative	[5]
ISIS 102660	DM6KUV9	Discovery agent	N.A.	Investigative	[5]
ISIS 102664	DMKI6L5	Discovery agent	N.A.	Investigative	[5]
ISIS 102668	DMY87QX	Discovery agent	N.A.	Investigative	[5]
ISIS 102676	DMFP598	Discovery agent	N.A.	Investigative	[5]
NM-PP1	DMS8H5Q	Discovery agent	N.A.	Investigative	[6]
Ro-4396686	DM5DMCH	Discovery agent	N.A.	Investigative	[7]

References

• [1] Joys of molecules. 2. Endeavors in chemical biology and medicinal chemistry. J Med Chem. 2005 Sep 8;48(18):5613-38. Address
• [2] Purine derivatives. US8846696.
• [3] 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.
• [4] Inhibition of forskolin-induced neurite outgrowth and protein phosphorylation by a newly synthesized selective inhibitor of cyclic AMP-dependent protein kinase, N-[2-(p-bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide (H-89), of PC12D pheochromocytoma cells. J Biol Chem. 1990 Mar 25;265(9):5267-72.
• [5] US patent application no. 6,248,586, Antisense modulation of PKA catalytic subunit C-alpha expression.
• [6] The selectivity of protein kinase inhibitors: a further update. Biochem J. 2007 Dec 15;408(3):297-315.
• [7] Biological evaluation of a multi-targeted small molecule inhibitor of tumor-induced angiogenesis. Bioorg Med Chem Lett. 2006 Apr 1;16(7):1950-3.