Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTYT1J6J)

• DOT Name: Phosphatidylinositol 3,4,5-trisphosphate-dependent Rac exchanger 2 protein (PREX2)
• Synonyms: P-Rex2; PtdIns(3,4,5)-dependent Rac exchanger 2; DEP domain-containing protein 2
• Gene Name: PREX2
• Related Disease:
  Melanoma
  Hepatocellular carcinoma
  Neoplasm
  Advanced cancer
  Breast cancer
  Breast carcinoma
  Carcinoma of liver and intrahepatic biliary tract
  Cutaneous melanoma
  Liver cancer
  Pancreatic ductal carcinoma
• UniProt ID: PREX2_HUMAN
• PDB ID: 6BNM
• Pfam ID: PF00610 ; PF00595 ; PF00169 ; PF00621
• Sequence:
  MSEDSRGDSRAESAKDLEKQLRLRVCVLSELQKTERDYVGTLEFLVSAFLHRMNQCAASK
  VDKNVTEETVKMLFSNIEDILAVHKEFLKVVEECLHPEPNAQQEVGTCFLHFKDKFRIYD
  EYCSNHEKAQKLLLELNKIRTIRTFLLNCMLLGGRKNTDVPLEGYLVTPIQRICKYPLIL
  KELLKRTPRKHSDYAAVMEALQAMKAVCSNINEAKRQMEKLEVLEEWQSHIEGWEGSNIT
  DTCTEMLMCGVLLKISSGNIQERVFFLFDNLLVYCKRKHRRLKNSKASTDGHRYLFRGRI
  NTEVMEVENVDDGTADFHSSGHIVVNGWKIHNTAKNKWFVCMAKTPEEKHEWFEAILKER
  ERRKGLKLGMEQDTWVMISEQGEKLYKMMCRQGNLIKDRKRKLTTFPKCFLGSEFVSWLL
  EIGEIHRPEEGVHLGQALLENGIIHHVTDKHQFKPEQMLYRFRYDDGTFYPRNEMQDVIS
  KGVRLYCRLHSLFTPVIRDKDYHLRTYKSVVMANKLIDWLIAQGDCRTREEAMIFGVGLC
  DNGFMHHVLEKSEFKDEPLLFRFFSDEEMEGSNMKHRLMKHDLKVVENVIAKSLLIKSNE
  GSYGFGLEDKNKVPIIKLVEKGSNAEMAGMEVGKKIFAINGDLVFMRPFNEVDCFLKSCL
  NSRKPLRVLVSTKPRETVKIPDSADGLGFQIRGFGPSVVHAVGRGTVAAAAGLHPGQCII
  KVNGINVSKETHASVIAHVTACRKYRRPTKQDSIQWVYNSIESAQEDLQKSHSKPPGDEA
  GDAFDCKVEEVIDKFNTMAIIDGKKEHVSLTVDNVHLEYGVVYEYDSTAGIKCNVVEKMI
  EPKGFFSLTAKILEALAKSDEHFVQNCTSLNSLNEVIPTDLQSKFSALCSERIEHLCQRI
  SSYKKFSRVLKNRAWPTFKQAKSKISPLHSSDFCPTNCHVNVMEVSYPKTSTSLGSAFGV
  QLDSRKHNSHDKENKSSEQGKLSPMVYIQHTITTMAAPSGLSLGQQDGHGLRYLLKEEDL
  ETQDIYQKLLGKLQTALKEVEMCVCQIDDLLSSITYSPKLERKTSEGIIPTDSDNEKGER
  NSKRVCFNVAGDEQEDSGHDTISNRDSYSDCNSNRNSIASFTSICSSQCSSYFHSDEMDS
  GDELPLSVRISHDKQDKIHSCLEHLFSQVDSITNLLKGQAVVRAFDQTKYLTPGRGLQEF
  QQEMEPKLSCPKRLRLHIKQDPWNLPSSVRTLAQNIRKFVEEVKCRLLLALLEYSDSETQ
  LRRDMVFCQTLVATVCAFSEQLMAALNQMFDNSKENEMETWEASRRWLDQIANAGVLFHF
  QSLLSPNLTDEQAMLEDTLVALFDLEKVSFYFKPSEEEPLVANVPLTYQAEGSRQALKVY
  FYIDSYHFEQLPQRLKNGGGFKIHPVLFAQALESMEGYYYRDNVSVEEFQAQINAASLEK
  VKQYNQKLRAFYLDKSNSPPNSTSKAAYVDKLMRPLNALDELYRLVASFIRSKRTAACAN
  TACSASGVGLLSVSSELCNRLGACHIIMCSSGVHRCTLSVTLEQAIILARSHGLPPRYIM
  QATDVMRKQGARVQNTAKNLGVRDRTPQSAPRLYKLCEPPPPAGEE
• Function: Functions as a RAC1 guanine nucleotide exchange factor (GEF), activating Rac proteins by exchanging bound GDP for free GTP. Its activity is synergistically activated by phosphatidylinositol 3,4,5-trisphosphate and the beta gamma subunits of heterotrimeric G protein. Mediates the activation of RAC1 in a PI3K-dependent manner. May be an important mediator of Rac signaling, acting directly downstream of both G protein-coupled receptors and phosphoinositide 3-kinase.
• Tissue Specificity: Isoform 1 is highly expressed in skeletal muscle, heart and placenta, absent from peripheral blood leukocytes. Isoform 2 is expressed in skeletal muscle, kidney, small intestine, and placenta. Isoform 3 is expressed in the heart.
• Reactome Pathway:
  RHOA GTPase cycle (R-HSA-8980692)
  CDC42 GTPase cycle (R-HSA-9013148)
  RAC1 GTPase cycle (R-HSA-9013149)
  Regulation of PTEN stability and activity (R-HSA-8948751)

Molecular Interaction Atlas (MIA) of This DOT

10 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Melanoma	DIS1RRCY	Definitive	Genetic Variation	[1]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[2]
Neoplasm	DISZKGEW	Strong	Altered Expression	[3]
Advanced cancer	DISAT1Z9	moderate	Genetic Variation	[4]
Breast cancer	DIS7DPX1	moderate	Biomarker	[4]
Breast carcinoma	DIS2UE88	Limited	Biomarker	[4]
Carcinoma of liver and intrahepatic biliary tract	DIS8WA0W	Limited	Altered Expression	[5]
Cutaneous melanoma	DIS3MMH9	Limited	Genetic Variation	[6]
Liver cancer	DISDE4BI	Limited	Altered Expression	[5]
Pancreatic ductal carcinoma	DIS26F9Q	Limited	Biomarker	[6]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Phosphatidylinositol 3,4,5-trisphosphate-dependent Rac exchanger 2 protein (PREX2).	[7]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Phosphatidylinositol 3,4,5-trisphosphate-dependent Rac exchanger 2 protein (PREX2).	[8]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Phosphatidylinositol 3,4,5-trisphosphate-dependent Rac exchanger 2 protein (PREX2).	[9]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of Phosphatidylinositol 3,4,5-trisphosphate-dependent Rac exchanger 2 protein (PREX2).	[10]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Phosphatidylinositol 3,4,5-trisphosphate-dependent Rac exchanger 2 protein (PREX2).	[11]
Clorgyline	DMCEUJD	Approved	Clorgyline increases the expression of Phosphatidylinositol 3,4,5-trisphosphate-dependent Rac exchanger 2 protein (PREX2).	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Phosphatidylinositol 3,4,5-trisphosphate-dependent Rac exchanger 2 protein (PREX2).	[13]

References

• [1] Somatic mutations of PREX2 gene in patients with hepatocellular carcinoma.Sci Rep. 2019 Feb 22;9(1):2552. doi: 10.1038/s41598-018-36810-5.
• [2] LncRNA MYCNOS facilitates proliferation and invasion in hepatocellular carcinoma by regulating miR-340.Hum Cell. 2020 Jan;33(1):148-158. doi: 10.1007/s13577-019-00303-y. Epub 2019 Nov 27.
• [3] Characterization of the GNMT-HectH9-PREX2 tripartite relationship in the pathogenesis of hepatocellular carcinoma.Int J Cancer. 2017 May 15;140(10):2284-2297. doi: 10.1002/ijc.30652.
• [4] P-Rex1 and P-Rex2 RacGEFs and cancer.Biochem Soc Trans. 2017 Aug 15;45(4):963-77. doi: 10.1042/BST20160269. Epub 2017 Jul 14.
• [5] The effect of CXCL9 on the invasion ability of hepatocellular carcinoma through up-regulation of PREX2.J Mol Histol. 2014 Dec;45(6):689-96. doi: 10.1007/s10735-014-9593-0. Epub 2014 Aug 24.
• [6] Truncating PREX2 mutations activate its GEF activity and alter gene expression regulation in NRAS-mutant melanoma.Proc Natl Acad Sci U S A. 2016 Mar 1;113(9):E1296-305. doi: 10.1073/pnas.1513801113. Epub 2016 Feb 16.
• [7] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [8] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [9] 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.
• [10] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [11] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [12] Anti-oncogenic and pro-differentiation effects of clorgyline, a monoamine oxidase A inhibitor, on high grade prostate cancer cells. BMC Med Genomics. 2009 Aug 20;2:55. doi: 10.1186/1755-8794-2-55.
• [13] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.