Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TT8QL1J)

• DTT Name: Protein kinase C theta (PRKCQ)
• Synonyms: Protein kinase C theta type; PRKCT; NPKC-theta
• Gene Name: PRKCQ
• DTT Type: Clinical trial target; [1]
• Related Disease: Transplant rejection [ICD-11: NE84]
• BioChemical Class: Kinase
• UniProt ID: KPCT_HUMAN
• TTD ID: T23995
• EC Number: EC 2.7.11.13
• Sequence:
  MSPFLRIGLSNFDCGSCQSCQGEAVNPYCAVLVKEYVESENGQMYIQKKPTMYPPWDSTF
  DAHINKGRVMQIIVKGKNVDLISETTVELYSLAERCRKNNGKTEIWLELKPQGRMLMNAR
  YFLEMSDTKDMNEFETEGFFALHQRRGAIKQAKVHHVKCHEFTATFFPQPTFCSVCHEFV
  WGLNKQGYQCRQCNAAIHKKCIDKVIAKCTGSAINSRETMFHKERFKIDMPHRFKVYNYK
  SPTFCEHCGTLLWGLARQGLKCDACGMNVHHRCQTKVANLCGINQKLMAEALAMIESTQQ
  ARCLRDTEQIFREGPVEIGLPCSIKNEARPPCLPTPGKREPQGISWESPLDEVDKMCHLP
  EPELNKERPSLQIKLKIEDFILHKMLGKGSFGKVFLAEFKKTNQFFAIKALKKDVVLMDD
  DVECTMVEKRVLSLAWEHPFLTHMFCTFQTKENLFFVMEYLNGGDLMYHIQSCHKFDLSR
  ATFYAAEIILGLQFLHSKGIVYRDLKLDNILLDKDGHIKIADFGMCKENMLGDAKTNTFC
  GTPDYIAPEILLGQKYNHSVDWWSFGVLLYEMLIGQSPFHGQDEEELFHSIRMDNPFYPR
  WLEKEAKDLLVKLFVREPEKRLGVRGDIRQHPLFREINWEELERKEIDPPFRPKVKSPFD
  CSNFDKEFLNEKPRLSFADRALINSMDQNMFRNFSFMNPGMERLIS
• Function: In TCR-CD3/CD28-co-stimulated T-cells, is required for the activation of NF-kappa-B and JUN, which in turn are essential for IL2 production, and participates in the calcium-dependent NFATC1 and NFATC2 transactivation. Mediates the activation of the canonical NF-kappa-B pathway (NFKB1) by direct phosphorylation of CARD11 on several serine residues, inducing CARD11 association with lipid rafts and recruitment of the BCL10-MALT1 complex, which then activates IKK complex, resulting in nuclear translocation and activation of NFKB1. May also play an indirect role in activation of the non-canonical NF-kappa-B (NFKB2) pathway. In the signaling pathway leading to JUN activation, acts by phosphorylating the mediator STK39/SPAK and may not act through MAP kinases signaling. Plays a critical role in TCR/CD28-induced NFATC1 and NFATC2 transactivation by participating in the regulation of reduced inositol 1,4,5-trisphosphate generation and intracellular calcium mobilization. After costimulation of T-cells through CD28 can phosphorylate CBLB and is required for the ubiquitination and subsequent degradation of CBLB, which is a prerequisite for the activation of TCR. During T-cells differentiation, plays an important role in the development of T-helper 2 (Th2) cells following immune and inflammatory responses, and, in the development of inflammatory autoimmune diseases, is necessary for the activation of IL17-producing Th17 cells. May play a minor role in Th1 response. Upon TCR stimulation, mediates T-cell protective survival signal by phosphorylating BAD, thus protecting T-cells from BAD-induced apoptosis, and by up-regulating BCL-X(L)/BCL2L1 levels through NF-kappa-B and JUN pathways. In platelets, regulates signal transduction downstream of the ITGA2B, CD36/GP4, F2R/PAR1 and F2RL3/PAR4 receptors, playing a positive role in 'outside-in' signaling and granule secretion signal transduction. May relay signals from the activated ITGA2B receptor by regulating the uncoupling of WASP and WIPF1, thereby permitting the regulation of actin filament nucleation and branching activity of the Arp2/3 complex. May mediate inhibitory effects of free fatty acids on insulin signaling by phosphorylating IRS1, which in turn blocks IRS1 tyrosine phosphorylation and downstream activation of the PI3K/AKT pathway. Phosphorylates MSN (moesin) in the presence of phosphatidylglycerol or phosphatidylinositol. Phosphorylates PDPK1 at 'Ser-504' and 'Ser-532' and negatively regulates its ability to phosphorylate PKB/AKT1. Calcium-independent, phospholipid- and diacylglycerol (DAG)-dependent serine/threonine-protein kinase that mediates non-redundant functions in T-cell receptor (TCR) signaling, including T-cells activation, proliferation, differentiation and survival, by mediating activation of multiple transcription factors such as NF-kappa-B, JUN, NFATC1 and NFATC2.
• KEGG Pathway:
  NF-kappa B signaling pathway (hsa04064)
  Vascular smooth muscle contraction (hsa04270)
  Tight junction (hsa04530)
  T cell receptor signaling pathway (hsa04660)
  Inflammatory mediator regulation of TRP channels (hsa04750)
  Adipocytokine signaling pathway (hsa04920)
  Measles (hsa05162)
• Reactome Pathway:
  Effects of PIP2 hydrolysis (R-HSA-114508)
  Inactivation, recovery and regulation of the phototransduction cascade (R-HSA-2514859)
  FCERI mediated NF-kB activation (R-HSA-2871837)
  G alpha (z) signalling events (R-HSA-418597)
  Apoptotic cleavage of cellular proteins (R-HSA-111465)

Molecular Interaction Atlas (MIA) of This DTT

1 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Sotrastaurin acetate	DME53YS	Renal transplantation	NE84	Phase 2	[1]

3 Discontinued Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
CDE-6960	DMA0DKI	Inflammation	1A00-CA43.1	Terminated	[2]
LY-317644	DMM20PI	N. A.	N. A.	Terminated	[3]
RO-320432	DMFZ1YW	N. A.	N. A.	Terminated	[4]

16 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
2,3,3-Triphenyl-acrylonitrile	DM7H34U	Discovery agent	N.A.	Investigative	[5]
2-(4-Hydroxy-phenyl)-3,3-diphenyl-acrylonitrile	DMNGW1A	Discovery agent	N.A.	Investigative	[5]
3,3-Bis-(4-hydroxy-phenyl)-2-phenyl-acrylonitrile	DMO51QG	Discovery agent	N.A.	Investigative	[5]
3,3-Bis-(4-methoxy-phenyl)-2-phenyl-acrylonitrile	DMZPYN2	Discovery agent	N.A.	Investigative	[5]
3-(4-Hydroxy-phenyl)-2,3-diphenyl-acrylonitrile	DME5238	Discovery agent	N.A.	Investigative	[5]
4-cycloheptyliden(4-hydroxyphenyl)methylphenol	DM4LIUC	Discovery agent	N.A.	Investigative	[5]
4-cyclohexyliden(4-hydroxyphenyl)methylphenol	DM8BLK2	Discovery agent	N.A.	Investigative	[5]
4-[1-(4-hydroxyphenyl)-3-methyl-1-butenyl]phenol	DM8IYG1	Discovery agent	N.A.	Investigative	[5]
L-serine-O-phosphate	DMTJ1NH	Discovery agent	N.A.	Investigative	[6]
LY-326449	DMN53M4	Discovery agent	N.A.	Investigative	[7]
Phosphonothreonine	DMTFHPI	Discovery agent	N.A.	Investigative	[6]
RO-316233	DMAGLPW	Discovery agent	N.A.	Investigative	[8]
Ro-32-0557	DMPVKEA	Discovery agent	N.A.	Investigative	[4]
[2,2':5',2'']Terthiophen-4-yl-methanol	DMRQC1F	Discovery agent	N.A.	Investigative	[9]
[2,2':5',2'']Terthiophene-4,5''-dicarbaldehyde	DMWDNLI	Discovery agent	N.A.	Investigative	[9]
[2,2':5',2'']Terthiophene-4-carbaldehyde	DM2S5EJ	Discovery agent	N.A.	Investigative	[9]

Molecular Expression Atlas (MEA) of This DTT

Disease Name	ICD 11	Studied Tissue	p-value	Fold-Change	Z-score
Breast cancer	2C82	Breast tissue	6.55E-09	0.05	0.16

References

• [1] Emerging drugs for psoriasis. Expert Opin Emerg Drugs. 2009 Mar;14(1):145-63.
• [2] Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800025002)
• [3] Synthesis of bisindolylmaleimide macrocycles, Bioorg. Med. Chem. Lett. 5(18):2093-2096 (1995).
• [4] Bisindolylmaleimide inhibitors of protein kinase C. Further conformational restriction of a tertiary amine side chain, Bioorg. Med. Chem. Lett. 4(11):1303-1308 (1994).
• [5] Multivariate analysis by the minimum spanning tree method of the structural determinants of diphenylethylenes and triphenylacrylonitriles implicate... J Med Chem. 1992 Feb 7;35(3):573-83.
• [6] How many drug targets are there Nat Rev Drug Discov. 2006 Dec;5(12):993-6.
• [7] (S)-13-[(dimethylamino)methyl]-10,11,14,15-tetrahydro-4,9:16, 21-dimetheno-1H, 13H-dibenzo[e,k]pyrrolo[3,4-h][1,4,13]oxadiazacyclohexadecene-1,3(2H... J Med Chem. 1996 Jul 5;39(14):2664-71.
• [8] Inhibitors of protein kinase C. 1. 2,3-Bisarylmaleimides. J Med Chem. 1992 Jan;35(1):177-84.
• [9] Novel protein kinase C inhibitors: synthesis and PKC inhibition of beta-substituted polythiophene derivatives. Bioorg Med Chem Lett. 1999 Aug 2;9(15):2279-82.