Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TT9QBI6)

• DTT Name: Phosphoinositide dependent protein kinase-1 (PDPK1)
• Synonyms: PDK1; HPDK1; 3-phosphoinositide-dependent protein kinase 1; 3-Phosphoinositide-dependent kinase-1; 3'-phosphoinositide dependent kinase 1
• Gene Name: PDPK1
• DTT Type: Clinical trial target; [1]
• BioChemical Class: Kinase
• UniProt ID: PDPK1_HUMAN
• TTD ID: T20891
• EC Number: EC 2.7.11.1
• Sequence:
  MARTTSQLYDAVPIQSSVVLCSCPSPSMVRTQTESSTPPGIPGGSRQGPAMDGTAAEPRP
  GAGSLQHAQPPPQPRKKRPEDFKFGKILGEGSFSTVVLARELATSREYAIKILEKRHIIK
  ENKVPYVTRERDVMSRLDHPFFVKLYFTFQDDEKLYFGLSYAKNGELLKYIRKIGSFDET
  CTRFYTAEIVSALEYLHGKGIIHRDLKPENILLNEDMHIQITDFGTAKVLSPESKQARAN
  SFVGTAQYVSPELLTEKSACKSSDLWALGCIIYQLVAGLPPFRAGNEYLIFQKIIKLEYD
  FPEKFFPKARDLVEKLLVLDATKRLGCEEMEGYGPLKAHPFFESVTWENLHQQTPPKLTA
  YLPAMSEDDEDCYGNYDNLLSQFGCMQVSSSSSSHSLSASDTGLPQRSGSNIEQYIHDLD
  SNSFELDLQFSEDEKRLLLEKQAGGNPWHQFVENNLILKMGPVDKRKGLFARRRQLLLTE
  GPHLYYVDPVNKVLKGEIPWSQELRPEAKNFKTFFVHTPNRTYYLMDPSGNAHKWCRKIQ
  EVWRQRYQSHPDAAVQ
• Function: Its targets include: protein kinase B (PKB/AKT1, PKB/AKT2, PKB/AKT3), p70 ribosomal protein S6 kinase (RPS6KB1), p90 ribosomal protein S6 kinase (RPS6KA1, RPS6KA2 and RPS6KA3), cyclic AMP-dependent protein kinase (PRKACA), protein kinase C (PRKCD and PRKCZ), serum and glucocorticoid-inducible kinase (SGK1, SGK2 and SGK3), p21-activated kinase-1 (PAK1), protein kinase PKN (PKN1 and PKN2). Plays a central role in the transduction of signals from insulin by providing the activating phosphorylation to PKB/AKT1, thus propagating the signal to downstream targets controlling cell proliferation and survival, as well as glucose and amino acid uptake and storage. Negatively regulates the TGF-beta-induced signaling by: modulating the association of SMAD3 and SMAD7 with TGF-beta receptor, phosphorylating SMAD2, SMAD3, SMAD4 and SMAD7, preventing the nuclear translocation of SMAD3 and SMAD4 and the translocation of SMAD7 from the nucleus to the cytoplasm in response to TGF-beta. Activates PPARG transcriptional activity and promotes adipocyte differentiation. Activates the NF-kappa-B pathway via phosphorylation of IKKB. The tyrosine phosphorylated form is crucial for the regulation of focal adhesions by angiotensin II. Controls proliferation, survival, and growth of developing pancreatic cells. Participates in the regulation of Ca(2+) entry and Ca(2+)-activated K(+) channels of mast cells. Essential for the motility of vascular endothelial cells (ECs) and is involved in the regulation of their chemotaxis. Plays a critical role in cardiac homeostasis by serving as a dual effector for cell survival and beta-adrenergic response. Plays an important role during thymocyte development by regulating the expression of key nutrient receptors on the surface of pre-T cells and mediating Notch-induced cell growth and proliferative responses. Provides negative feedback inhibition to toll-like receptor-mediated NF-kappa-B activation in macrophages. Isoform 3 is catalytically inactive. Serine/threonine kinase which acts as a master kinase, phosphorylating and activating a subgroup of the AGC family of protein kinases.
• KEGG Pathway:
  PPAR signaling pathway (hsa03320)
  FoxO signaling pathway (hsa04068)
  Sphingolipid signaling pathway (hsa04071)
  mTOR signaling pathway (hsa04150)
  PI3K-Akt signaling pathway (hsa04151)
  AMPK signaling pathway (hsa04152)
  Focal adhesion (hsa04510)
  T cell receptor signaling pathway (hsa04660)
  Fc epsilon RI signaling pathway (hsa04664)
  Neurotrophin signaling pathway (hsa04722)
  Insulin signaling pathway (hsa04910)
  Thyroid hormone signaling pathway (hsa04919)
  Aldosterone-regulated sodium reabsorption (hsa04960)
  Toxoplasmosis (hsa05145)
  Hepatitis C (hsa05160)
  Proteoglycans in cancer (hsa05205)
  Endometrial cancer (hsa05213)
  Prostate cancer (hsa05215)
  Non-small cell lung cancer (hsa05223)
  Choline metabolism in cancer (hsa05231)
• Reactome Pathway:
  PIP3 activates AKT signaling (R-HSA-1257604)
  Activation of AKT2 (R-HSA-165158)
  Role of LAT2/NTAL/LAB on calcium mobilization (R-HSA-2730905)
  FCERI mediated NF-kB activation (R-HSA-2871837)
  Integrin alphaIIb beta3 signaling (R-HSA-354192)
  CD28 dependent PI3K/Akt signaling (R-HSA-389357)
  CTLA4 inhibitory signaling (R-HSA-389513)
  G beta (R-HSA-392451)
  VEGFR2 mediated vascular permeability (R-HSA-5218920)
  VEGFR2 mediated cell proliferation (R-HSA-5218921)
  CLEC7A (Dectin-1) signaling (R-HSA-5607764)
  RHO GTPases activate PKNs (R-HSA-5625740)
  Constitutive Signaling by AKT1 E17K in Cancer (R-HSA-5674400)
  GPVI-mediated activation cascade (R-HSA-114604)

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
AR-12	DM4RK6P	Lymphoma	2A80-2A86	Phase 1	[1]

7 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
BX-795	DMRIMLJ	Discovery agent	N.A.	Investigative	[2]
BX-912	DMZA45C	Discovery agent	N.A.	Investigative	[2]
GSK-2334470	DM3BI7R	Solid tumour/cancer	2A00-2F9Z	Investigative	[3]
L-serine-O-phosphate	DMTJ1NH	Discovery agent	N.A.	Investigative	[4]
PF-5177624	DMUOFT0	Solid tumour/cancer	2A00-2F9Z	Investigative	[5]
PHT-427	DMI96Y3	Discovery agent	N.A.	Investigative	[6]
PMID20005102C1	DMMESBW	Discovery agent	N.A.	Investigative	[7]

References

• [1] Interpreting expression profiles of cancers by genome-wide survey of breadth of expression in normal tissues. Genomics 2005 Aug;86(2):127-41.
• [2] Novel small molecule inhibitors of 3-phosphoinositide-dependent kinase-1. J Biol Chem. 2005 May 20;280(20):19867-74.
• [3] Genetic inactivation or pharmacological inhibition of Pdk1 delays development and inhibits metastasis of Braf(V600E)::Pten(-/-) melanoma. Oncogene. 2014 Aug 21;33(34):4330-9.
• [4] How many drug targets are there Nat Rev Drug Discov. 2006 Dec;5(12):993-6.
• [5] Targeting 3-phosphoinoside-dependent kinase-1 to inhibit insulin-like growth factor-I induced AKT and p70 S6 kinase activation in breast cancer cells. PLoS One. 2012;7(10):e48402.
• [6] Molecular pharmacology and antitumor activity of PHT-427, a novel Akt/phosphatidylinositide-dependent protein kinase 1 pleckstrin homology domain inhibitor. Mol Cancer Ther. 2010 Mar;9(3):706-17.
• [7] 2,3,5-Trisubstituted pyridines as selective AKT inhibitors. Part II: Improved drug-like properties and kinase selectivity from azaindazoles. Bioorg Med Chem Lett. 2010 Jan 15;20(2):679-83.