Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTT09ZVP)

• DOT Name: 3-phosphoinositide-dependent protein kinase 1 (PDPK1)
• Synonyms: hPDK1; EC 2.7.11.1
• Gene Name: PDPK1
• UniProt ID: PDPK1_HUMAN
• PDB ID: 1H1W ; 1OKY ; 1OKZ ; 1UU3 ; 1UU7 ; 1UU8 ; 1UU9 ; 1UVR ; 1W1D ; 1W1G ; 1W1H ; 1Z5M ; 2BIY ; 2PE0 ; 2PE1 ; 2PE2 ; 2R7B ; 2VKI ; 2XCH ; 2XCK ; 3H9O ; 3HRC ; 3HRF ; 3ION ; 3IOP ; 3NAX ; 3NAY ; 3NUN ; 3NUS ; 3NUU ; 3NUY ; 3ORX ; 3ORZ ; 3OTU ; 3PWY ; 3QC4 ; 3QCQ ; 3QCS ; 3QCX ; 3QCY ; 3QD0 ; 3QD3 ; 3QD4 ; 3RCJ ; 3RWP ; 3RWQ ; 3SC1 ; 4A06 ; 4A07 ; 4AW0 ; 4AW1 ; 4CT1 ; 4CT2 ; 4RQK ; 4RQV ; 4RRV ; 4XX9 ; 5ACK ; 5HKM ; 5HNG ; 5HO7 ; 5HO8 ; 5LVL ; 5LVM ; 5LVN ; 5LVO ; 5LVP ; 5MRD ; 6WJQ ; 8DQT
• EC Number: 2.7.11.1
• Pfam ID: PF14593 ; PF00069
• Sequence:
  MARTTSQLYDAVPIQSSVVLCSCPSPSMVRTQTESSTPPGIPGGSRQGPAMDGTAAEPRP
  GAGSLQHAQPPPQPRKKRPEDFKFGKILGEGSFSTVVLARELATSREYAIKILEKRHIIK
  ENKVPYVTRERDVMSRLDHPFFVKLYFTFQDDEKLYFGLSYAKNGELLKYIRKIGSFDET
  CTRFYTAEIVSALEYLHGKGIIHRDLKPENILLNEDMHIQITDFGTAKVLSPESKQARAN
  SFVGTAQYVSPELLTEKSACKSSDLWALGCIIYQLVAGLPPFRAGNEYLIFQKIIKLEYD
  FPEKFFPKARDLVEKLLVLDATKRLGCEEMEGYGPLKAHPFFESVTWENLHQQTPPKLTA
  YLPAMSEDDEDCYGNYDNLLSQFGCMQVSSSSSSHSLSASDTGLPQRSGSNIEQYIHDLD
  SNSFELDLQFSEDEKRLLLEKQAGGNPWHQFVENNLILKMGPVDKRKGLFARRRQLLLTE
  GPHLYYVDPVNKVLKGEIPWSQELRPEAKNFKTFFVHTPNRTYYLMDPSGNAHKWCRKIQ
  EVWRQRYQSHPDAAVQ
• Function: Serine/threonine kinase which acts as a master kinase, phosphorylating and activating a subgroup of the AGC family of protein kinases. 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.
• Tissue Specificity: Appears to be expressed ubiquitously. The Tyr-9 phosphorylated form is markedly increased in diseased tissue compared with normal tissue from lung, liver, colon and breast.
• KEGG Pathway:
  Platinum drug resistance (hsa01524)
  PPAR sig.ling pathway (hsa03320)
  FoxO sig.ling pathway (hsa04068)
  Sphingolipid sig.ling pathway (hsa04071)
  Autophagy - animal (hsa04140)
  mTOR sig.ling pathway (hsa04150)
  PI3K-Akt sig.ling pathway (hsa04151)
  AMPK sig.ling pathway (hsa04152)
  Apoptosis (hsa04210)
  Axon guidance (hsa04360)
  Focal adhesion (hsa04510)
  T cell receptor sig.ling pathway (hsa04660)
  Fc epsilon RI sig.ling pathway (hsa04664)
  Neurotrophin sig.ling pathway (hsa04722)
  Insulin sig.ling pathway (hsa04910)
  Thyroid hormone sig.ling pathway (hsa04919)
  Insulin resistance (hsa04931)
  Aldosterone-regulated sodium reabsorption (hsa04960)
  Toxoplasmosis (hsa05145)
  Proteoglycans in cancer (hsa05205)
  Chemical carcinogenesis - reactive oxygen species (hsa05208)
  Endometrial cancer (hsa05213)
  Prostate cancer (hsa05215)
  Non-small cell lung cancer (hsa05223)
  Choline metabolism in cancer (hsa05231)
  Lipid and atherosclerosis (hsa05417)
• Reactome Pathway:
  PIP3 activates AKT signaling (R-HSA-1257604)
  Activation of AKT2 (R-HSA-165158)
  Downstream TCR signaling (R-HSA-202424)
  Role of LAT2/NTAL/LAB on calcium mobilization (R-HSA-2730905)
  FCERI mediated NF-kB activation (R-HSA-2871837)
  Integrin signaling (R-HSA-354192)
  CD28 dependent PI3K/Akt signaling (R-HSA-389357)
  G beta (R-HSA-392451)
  RSK activation (R-HSA-444257)
  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)
  Regulation of TP53 Degradation (R-HSA-6804757)
  Estrogen-stimulated signaling through PRKCZ (R-HSA-9634635)
  SARS-CoV-1 targets host intracellular signalling and regulatory pathways (R-HSA-9735871)
  SARS-CoV-2 targets host intracellular signalling and regulatory pathways (R-HSA-9755779)
  GPVI-mediated activation cascade (R-HSA-114604)

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Drug Response of 4 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	3-phosphoinositide-dependent protein kinase 1 (PDPK1) decreases the response to substance of Doxorubicin.	[24]
Paclitaxel	DMLB81S	Approved	3-phosphoinositide-dependent protein kinase 1 (PDPK1) decreases the response to substance of Paclitaxel.	[24]
Gemcitabine	DMSE3I7	Approved	3-phosphoinositide-dependent protein kinase 1 (PDPK1) decreases the response to substance of Gemcitabine.	[24]
AR-12	DM4RK6P	Phase 1	3-phosphoinositide-dependent protein kinase 1 (PDPK1) decreases the response to substance of AR-12.	[25]

18 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of 3-phosphoinositide-dependent protein kinase 1 (PDPK1).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of 3-phosphoinositide-dependent protein kinase 1 (PDPK1).	[2]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of 3-phosphoinositide-dependent protein kinase 1 (PDPK1).	[3]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of 3-phosphoinositide-dependent protein kinase 1 (PDPK1).	[4]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of 3-phosphoinositide-dependent protein kinase 1 (PDPK1).	[5]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the activity of 3-phosphoinositide-dependent protein kinase 1 (PDPK1).	[6]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of 3-phosphoinositide-dependent protein kinase 1 (PDPK1).	[7]
Diclofenac	DMPIHLS	Approved	Diclofenac affects the expression of 3-phosphoinositide-dependent protein kinase 1 (PDPK1).	[7]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of 3-phosphoinositide-dependent protein kinase 1 (PDPK1).	[9]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of 3-phosphoinositide-dependent protein kinase 1 (PDPK1).	[12]
UCN-01	DMUNJZB	Phase 2	UCN-01 decreases the activity of 3-phosphoinositide-dependent protein kinase 1 (PDPK1).	[13]
PMID26394986-Compound-22	DM43Z1G	Patented	PMID26394986-Compound-22 decreases the activity of 3-phosphoinositide-dependent protein kinase 1 (PDPK1).	[17]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of 3-phosphoinositide-dependent protein kinase 1 (PDPK1).	[18]
Glyphosate	DM0AFY7	Investigative	Glyphosate decreases the expression of 3-phosphoinositide-dependent protein kinase 1 (PDPK1).	[19]
Maleic Acid	DM4L0R7	Investigative	Maleic Acid decreases the expression of 3-phosphoinositide-dependent protein kinase 1 (PDPK1).	[21]
G6976	DMEZO4M	Investigative	G6976 decreases the activity of 3-phosphoinositide-dependent protein kinase 1 (PDPK1).	[13]
BX-795	DMRIMLJ	Investigative	BX-795 decreases the activity of 3-phosphoinositide-dependent protein kinase 1 (PDPK1).	[23]
STAUROSPORINONE	DMU2H4K	Investigative	STAUROSPORINONE decreases the activity of 3-phosphoinositide-dependent protein kinase 1 (PDPK1).	[13]

8 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Amiloride	DMRTSGP	Approved	Amiloride decreases the phosphorylation of 3-phosphoinositide-dependent protein kinase 1 (PDPK1).	[8]
Curcumin	DMQPH29	Phase 3	Curcumin decreases the phosphorylation of 3-phosphoinositide-dependent protein kinase 1 (PDPK1).	[10]
Rigosertib	DMOSTXF	Phase 3	Rigosertib decreases the phosphorylation of 3-phosphoinositide-dependent protein kinase 1 (PDPK1).	[11]
PF-04991532	DM94NBE	Phase 2	PF-04991532 decreases the phosphorylation of 3-phosphoinositide-dependent protein kinase 1 (PDPK1).	[14]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of 3-phosphoinositide-dependent protein kinase 1 (PDPK1).	[15]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of 3-phosphoinositide-dependent protein kinase 1 (PDPK1).	[16]
Microcystin-LR	DMTMLRN	Investigative	Microcystin-LR increases the phosphorylation of 3-phosphoinositide-dependent protein kinase 1 (PDPK1).	[20]
Icariside II	DM3DB8X	Investigative	Icariside II decreases the phosphorylation of 3-phosphoinositide-dependent protein kinase 1 (PDPK1).	[22]

References

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• [18] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.
• [19] Glyphosate-based herbicides at low doses affect canonical pathways in estrogen positive and negative breast cancer cell lines. PLoS One. 2019 Jul 11;14(7):e0219610. doi: 10.1371/journal.pone.0219610. eCollection 2019.
• [20] p53 Plays an important role in cell fate determination after exposure to microcystin-LR. Environ Health Perspect. 2010 Sep;118(9):1292-8. doi: 10.1289/ehp.1001899. Epub 2010 Apr 26.
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• [25] From the cyclooxygenase-2 inhibitor celecoxib to a novel class of 3-phosphoinositide-dependent protein kinase-1 inhibitors. Cancer Res. 2004 Jun 15;64(12):4309-18. doi: 10.1158/0008-5472.CAN-03-4063.