Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT3U3X8Z)

• DOT Name: Sister chromatid cohesion protein PDS5 homolog B (PDS5B)
• Synonyms: Androgen-induced proliferation inhibitor; Androgen-induced prostate proliferative shutoff-associated protein AS3
• Gene Name: PDS5B
• Related Disease:
  Breast carcinoma
  Cardiac failure
  Cleft palate
  Colorectal carcinoma
  Congestive heart failure
  Cornelia de Lange syndrome
  Gestational trophoblastic neoplasia
  Isolated cleft palate
  Prostate cancer
  Prostate carcinoma
  Breast cancer
  Carcinoma
  Coronary heart disease
  Pancreatic cancer
  Lung carcinoma
  Lung squamous cell carcinoma
  Neoplasm
• UniProt ID: PDS5B_HUMAN
• PDB ID: 5HDT
• Pfam ID: PF20168
• Sequence:
  MAHSKTRTNDGKITYPPGVKEISDKISKEEMVRRLKMVVKTFMDMDQDSEEEKELYLNLA
  LHLASDFFLKHPDKDVRLLVACCLADIFRIYAPEAPYTSPDKLKDIFMFITRQLKGLEDT
  KSPQFNRYFYLLENIAWVKSYNICFELEDSNEIFTQLYRTLFSVINNGHNQKVHMHMVDL
  MSSIICEGDTVSQELLDTVLVNLVPAHKNLNKQAYDLAKALLKRTAQAIEPYITNFFNQV
  LMLGKTSISDLSEHVFDLILELYNIDSHLLLSVLPQLEFKLKSNDNEERLQVVKLLAKMF
  GAKDSELASQNKPLWQCYLGRFNDIHVPIRLECVKFASHCLMNHPDLAKDLTEYLKVRSH
  DPEEAIRHDVIVSIVTAAKKDILLVNDHLLNFVRERTLDKRWRVRKEAMMGLAQIYKKYA
  LQSAAGKDAAKQIAWIKDKLLHIYYQNSIDDRLLVERIFAQYMVPHNLETTERMKCLYYL
  YATLDLNAVKALNEMWKCQNLLRHQVKDLLDLIKQPKTDASVKAIFSKVMVITRNLPDPG
  KAQDFMKKFTQVLEDDEKIRKQLEVLVSPTCSCKQAEGCVREITKKLGNPKQPTNPFLEM
  IKFLLERIAPVHIDTESISALIKQVNKSIDGTADDEDEGVPTDQAIRAGLELLKVLSFTH
  PISFHSAETFESLLACLKMDDEKVAEAALQIFKNTGSKIEEDFPHIRSALLPVLHHKSKK
  GPPRQAKYAIHCIHAIFSSKETQFAQIFEPLHKSLDPSNLEHLITPLVTIGHIALLAPDQ
  FAAPLKSLVATFIVKDLLMNDRLPGKKTTKLWVPDEEVSPETMVKIQAIKMMVRWLLGMK
  NNHSKSGTSTLRLLTTILHSDGDLTEQGKISKPDMSRLRLAAGSAIVKLAQEPCYHEIIT
  LEQYQLCALAINDECYQVRQVFAQKLHKGLSRLRLPLEYMAICALCAKDPVKERRAHARQ
  CLVKNINVRREYLKQHAAVSEKLLSLLPEYVVPYTIHLLAHDPDYVKVQDIEQLKDVKEC
  LWFVLEILMAKNENNSHAFIRKMVENIKQTKDAQGPDDAKMNEKLYTVCDVAMNIIMSKS
  TTYSLESPKDPVLPARFFTQPDKNFSNTKNYLPPEMKSFFTPGKPKTTNVLGAVNKPLSS
  AGKQSQTKSSRMETVSNASSSSNPSSPGRIKGRLDSSEMDHSENEDYTMSSPLPGKKSDK
  RDDSDLVRSELEKPRGRKKTPVTEQEEKLGMDDLTKLVQEQKPKGSQRSRKRGHTASESD
  EQQWPEEKRLKEDILENEDEQNSPPKKGKRGRPPKPLGGGTPKEEPTMKTSKKGSKKKSG
  PPAPEEEEEEERQSGNTEQKSKSKQHRVSRRAQQRAESPESSAIESTQSTPQKGRGRPSK
  TPSPSQPKKNVRVGRSKQAATKENDSSEEVDVFQGSSPVDDIPQEETEEEEVSTVNVRRR
  SAKRERR
• Function: Regulator of sister chromatid cohesion in mitosis which may stabilize cohesin complex association with chromatin. May couple sister chromatid cohesion during mitosis to DNA replication. Cohesion ensures that chromosome partitioning is accurate in both meiotic and mitotic cells and plays an important role in DNA repair. Plays a role in androgen-induced proliferative arrest in prostate cells.
• Tissue Specificity: Widely expressed.
• KEGG Pathway: Cell cycle (hsa04110)
• Reactome Pathway:
  Establishment of Sister Chromatid Cohesion (R-HSA-2468052)
  Cohesin Loading onto Chromatin (R-HSA-2470946)
  Resolution of Sister Chromatid Cohesion (R-HSA-2500257)
  Separation of Sister Chromatids (R-HSA-2467813)

Molecular Interaction Atlas (MIA) of This DOT

17 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Breast carcinoma	DIS2UE88	Strong	Genetic Variation	[1]
Cardiac failure	DISDC067	Strong	Genetic Variation	[2]
Cleft palate	DIS6G5TF	Strong	Biomarker	[2]
Colorectal carcinoma	DIS5PYL0	Strong	Genetic Variation	[3]
Congestive heart failure	DIS32MEA	Strong	Genetic Variation	[2]
Cornelia de Lange syndrome	DISEQSXO	Strong	Genetic Variation	[2]
Gestational trophoblastic neoplasia	DIS4EJNA	Strong	Biomarker	[4]
Isolated cleft palate	DISV80CD	Strong	Biomarker	[2]
Prostate cancer	DISF190Y	Strong	Biomarker	[5]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[5]
Breast cancer	DIS7DPX1	moderate	Altered Expression	[6]
Carcinoma	DISH9F1N	moderate	Biomarker	[7]
Coronary heart disease	DIS5OIP1	moderate	Genetic Variation	[8]
Pancreatic cancer	DISJC981	moderate	Altered Expression	[9]
Lung carcinoma	DISTR26C	Limited	Genetic Variation	[10]
Lung squamous cell carcinoma	DISXPIBD	Limited	Genetic Variation	[10]
Neoplasm	DISZKGEW	Limited	Genetic Variation	[11]

12 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 Sister chromatid cohesion protein PDS5 homolog B (PDS5B).	[12]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Sister chromatid cohesion protein PDS5 homolog B (PDS5B).	[13]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Sister chromatid cohesion protein PDS5 homolog B (PDS5B).	[14]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Sister chromatid cohesion protein PDS5 homolog B (PDS5B).	[15]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Sister chromatid cohesion protein PDS5 homolog B (PDS5B).	[16]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Sister chromatid cohesion protein PDS5 homolog B (PDS5B).	[17]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Sister chromatid cohesion protein PDS5 homolog B (PDS5B).	[18]
Demecolcine	DMCZQGK	Approved	Demecolcine increases the expression of Sister chromatid cohesion protein PDS5 homolog B (PDS5B).	[19]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Sister chromatid cohesion protein PDS5 homolog B (PDS5B).	[20]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Sister chromatid cohesion protein PDS5 homolog B (PDS5B).	[22]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Sister chromatid cohesion protein PDS5 homolog B (PDS5B).	[25]
[3H]methyltrienolone	DMTSGOW	Investigative	[3H]methyltrienolone increases the expression of Sister chromatid cohesion protein PDS5 homolog B (PDS5B).	[26]

1 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
DNCB	DMDTVYC	Phase 2	DNCB affects the binding of Sister chromatid cohesion protein PDS5 homolog B (PDS5B).	[21]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
TAK-243	DM4GKV2	Phase 1	TAK-243 decreases the sumoylation of Sister chromatid cohesion protein PDS5 homolog B (PDS5B).	[23]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Sister chromatid cohesion protein PDS5 homolog B (PDS5B).	[24]
Coumarin	DM0N8ZM	Investigative	Coumarin affects the phosphorylation of Sister chromatid cohesion protein PDS5 homolog B (PDS5B).	[24]

References

• [1] Association analysis identifies 65 new breast cancer risk loci.Nature. 2017 Nov 2;551(7678):92-94. doi: 10.1038/nature24284. Epub 2017 Oct 23.
• [2] Dosage effects of cohesin regulatory factor PDS5 on mammalian development: implications for cohesinopathies.PLoS One. 2009;4(5):e5232. doi: 10.1371/journal.pone.0005232. Epub 2009 May 1.
• [3] Frameshift mutations of chromosome cohesion-related genes SGOL1 and PDS5B in gastric and colorectal cancers with high microsatellite instability.Hum Pathol. 2013 Oct;44(10):2234-40. doi: 10.1016/j.humpath.2013.04.017. Epub 2013 Jul 12.
• [4] Hepatic toxicity following actinomycin D chemotherapy in treatment of familial gestational trophoblastic neoplasia: A case report.Medicine (Baltimore). 2018 Sep;97(38):e12424. doi: 10.1097/MD.0000000000012424.
• [5] Correlation of genomic and expression alterations of AS3 with esophageal squamous cell carcinoma.J Genet Genomics. 2008 May;35(5):267-71. doi: 10.1016/S1673-8527(08)60038-7.
• [6] APRIN is a cell cycle specific BRCA2-interacting protein required for genome integrity and a predictor of outcome after chemotherapy in breast cancer.EMBO J. 2012 Mar 7;31(5):1160-76. doi: 10.1038/emboj.2011.490. Epub 2012 Jan 31.
• [7] Cohesin subunits, STAG1 and STAG2, and cohesin regulatory factor, PDS5b, in oral squamous cells carcinomas.J Oral Pathol Med. 2017 Mar;46(3):188-193. doi: 10.1111/jop.12474. Epub 2016 Jun 24.
• [8] Identification of 64 Novel Genetic Loci Provides an Expanded View on the Genetic Architecture of Coronary Artery Disease.Circ Res. 2018 Feb 2;122(3):433-443. doi: 10.1161/CIRCRESAHA.117.312086. Epub 2017 Dec 6.
• [9] PDS5B regulates cell proliferation and motility via upregulation of Ptch2 in pancreatic cancer cells.Cancer Lett. 2019 Sep 28;460:65-74. doi: 10.1016/j.canlet.2019.06.014. Epub 2019 Jun 22.
• [10] Large-scale association analysis identifies new lung cancer susceptibility loci and heterogeneity in genetic susceptibility across histological subtypes.Nat Genet. 2017 Jul;49(7):1126-1132. doi: 10.1038/ng.3892. Epub 2017 Jun 12.
• [11] Genomic analysis of germ line and somatic variants in familial myelodysplasia/acute myeloid leukemia.Blood. 2015 Nov 26;126(22):2484-90. doi: 10.1182/blood-2015-04-641100. Epub 2015 Oct 22.
• [12] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [13] 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.
• [14] 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.
• [15] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [16] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [17] Persistent and non-persistent changes in gene expression result from long-term estrogen exposure of MCF-7 breast cancer cells. J Steroid Biochem Mol Biol. 2011 Feb;123(3-5):140-50.
• [18] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [19] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [20] 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.
• [21] Proteomic analysis of the cellular response to a potent sensitiser unveils the dynamics of haptenation in living cells. Toxicology. 2020 Dec 1;445:152603. doi: 10.1016/j.tox.2020.152603. Epub 2020 Sep 28.
• [22] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [23] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [24] 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.
• [25] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [26] Analysis of the prostate cancer cell line LNCaP transcriptome using a sequencing-by-synthesis approach. BMC Genomics. 2006 Sep 29;7:246. doi: 10.1186/1471-2164-7-246.