Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT21CROX)

• DOT Name: p21-activated protein kinase-interacting protein 1 (PAK1IP1)
• Synonyms: PAK/PLC-interacting protein 1; hPIP1; PAK1-interacting protein 1; WD repeat-containing protein 84
• Gene Name: PAK1IP1
• UniProt ID: PK1IP_HUMAN
• Pfam ID: PF00400
• Sequence:
  MELVAGCYEQVLFGFAVHPEPEACGDHEQWTLVADFTHHAHTASLSAVAVNSRFVVTGSK
  DETIHIYDMKKKIEHGALVHHSGTITCLKFYGNRHLISGAEDGLICIWDAKKWECLKSIK
  AHKGQVTFLSIHPSGKLALSVGTDKTLRTWNLVEGRSAFIKNIKQNAHIVEWSPRGEQYV
  VIIQNKIDIYQLDTASISGTITNEKRISSVKFLSESVLAVAGDEEVIRFFDCDSLVCLCE
  FKAHENRVKDMFSFEIPEHHVIVSASSDGFIKMWKLKQDKKVPPSLLCEINTNARLTCLG
  VWLDKVADMKESLPPAAEPSPVSKEQSKIGKKEPGDTVHKEEKRSKPNTKKRGLTGDSKK
  ATKESGLISTKKRKMVEMLEKKRKKKKIKTMQ
• Function: Negatively regulates the PAK1 kinase. PAK1 is a member of the PAK kinase family, which has been shown to play a positive role in the regulation of signaling pathways involving MAPK8 and RELA. PAK1 exists as an inactive homodimer, which is activated by binding of small GTPases such as CDC42 to an N-terminal regulatory domain. PAK1IP1 also binds to the N-terminus of PAK1, and inhibits the specific activation of PAK1 by CDC42. May be involved in ribosomal large subunit assembly.
• Tissue Specificity: Expressed in brain, colon, heart, kidney, liver, lung, muscle, peripheral blood leukocytes, placenta, small intestine, spleen and thymus.

Molecular Interaction Atlas (MIA) of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of p21-activated protein kinase-interacting protein 1 (PAK1IP1).	[1]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of p21-activated protein kinase-interacting protein 1 (PAK1IP1).	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of p21-activated protein kinase-interacting protein 1 (PAK1IP1).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of p21-activated protein kinase-interacting protein 1 (PAK1IP1).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of p21-activated protein kinase-interacting protein 1 (PAK1IP1).	[4]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of p21-activated protein kinase-interacting protein 1 (PAK1IP1).	[5]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of p21-activated protein kinase-interacting protein 1 (PAK1IP1).	[6]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of p21-activated protein kinase-interacting protein 1 (PAK1IP1).	[7]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of p21-activated protein kinase-interacting protein 1 (PAK1IP1).	[8]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of p21-activated protein kinase-interacting protein 1 (PAK1IP1).	[8]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of p21-activated protein kinase-interacting protein 1 (PAK1IP1).	[9]
Progesterone	DMUY35B	Approved	Progesterone decreases the expression of p21-activated protein kinase-interacting protein 1 (PAK1IP1).	[10]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of p21-activated protein kinase-interacting protein 1 (PAK1IP1).	[11]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of p21-activated protein kinase-interacting protein 1 (PAK1IP1).	[12]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of p21-activated protein kinase-interacting protein 1 (PAK1IP1).	[13]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of p21-activated protein kinase-interacting protein 1 (PAK1IP1).	[15]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of p21-activated protein kinase-interacting protein 1 (PAK1IP1).	[16]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of p21-activated protein kinase-interacting protein 1 (PAK1IP1).	[17]

References

• [1] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [2] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [3] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [4] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [5] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [6] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [7] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [8] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [9] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [10] Gene expression in endometrial cancer cells (Ishikawa) after short time high dose exposure to progesterone. Steroids. 2008 Jan;73(1):116-28.
• [11] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [12] LSD1 activates a lethal prostate cancer gene network independently of its demethylase function. Proc Natl Acad Sci U S A. 2018 May 1;115(18):E4179-E4188.
• [13] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [14] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [15] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [16] 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.
• [17] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.