Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT7ZRW2F)

• DOT Name: ProSAAS (PCSK1N)
• Synonyms: Proprotein convertase subtilisin/kexin type 1 inhibitor; Proprotein convertase 1 inhibitor; pro-SAAS
• Gene Name: PCSK1N
• Related Disease:
  Advanced cancer
  Alzheimer disease
  Drug dependence
  Fibromyalgia
  Mental disorder
  Pick disease
  Breast cancer
  Breast carcinoma
  Eating disorder
  Small-cell lung cancer
  Anxiety
  Anxiety disorder
  High blood pressure
  Neoplasm
  Obesity
  Type-1 diabetes
• UniProt ID: PCS1N_HUMAN
• Pfam ID: PF07259
• Sequence:
  MAGSPLLWGPRAGGVGLLVLLLLGLFRPPPALCARPVKEPRGLSAASPPLAETGAPRRFR
  RSVPRGEAAGAVQELARALAHLLEAERQERARAEAQEAEDQQARVLAQLLRVWGAPRNSD
  PALGLDDDPDAPAAQLARALLRARLDPAALAAQLVPAPVPAAALRPRPPVYDDGPAGPDA
  EEAGDETPDVDPELLRYLLGRILAGSADSEGVAAPRRLRRAADHDVGSELPPEGVLGALL
  RVKRLETPAPQVPARRLLPP
• Function: May function in the control of the neuroendocrine secretory pathway. Proposed be a specific endogenous inhibitor of PCSK1. ProSAAS and Big PEN-LEN, both containing the C-terminal inhibitory domain, but not the further processed peptides reduce PCSK1 activity in the endoplasmic reticulum and Golgi. It reduces the activity of the 84 kDa form but not the autocatalytically derived 66 kDa form of PCSK1. Subsequent processing of proSAAS may eliminate the inhibition. Slows down convertase-mediated processing of proopiomelanocortin and proenkephalin. May control the intracellular timing of PCSK1 rather than its total level of activity; [Big LEN]: Endogenous ligand for GPR171. Neuropeptide involved in the regulation of feeding; [PEN]: Endogenous ligand for GPR171. Neuropeptide involved in the regulation of feeding.
• Tissue Specificity: Expressed in brain and pancreas.

Molecular Interaction Atlas (MIA) of This DOT

16 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Alzheimer disease	DISF8S70	Strong	Biomarker	[2]
Drug dependence	DIS9IXRC	Strong	Biomarker	[3]
Fibromyalgia	DISZJDS2	Strong	Altered Expression	[4]
Mental disorder	DIS3J5R8	Strong	Biomarker	[5]
Pick disease	DISP6X50	Strong	Biomarker	[6]
Breast cancer	DIS7DPX1	moderate	Biomarker	[7]
Breast carcinoma	DIS2UE88	moderate	Biomarker	[7]
Eating disorder	DISVGXN0	moderate	Biomarker	[8]
Small-cell lung cancer	DISK3LZD	moderate	Altered Expression	[9]
Anxiety	DISIJDBA	Limited	Altered Expression	[10]
Anxiety disorder	DISBI2BT	Limited	Altered Expression	[10]
High blood pressure	DISY2OHH	Limited	Biomarker	[11]
Neoplasm	DISZKGEW	Limited	Altered Expression	[12]
Obesity	DIS47Y1K	Limited	Biomarker	[13]
Type-1 diabetes	DIS7HLUB	Limited	Genetic Variation	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of ProSAAS (PCSK1N).	[15]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of ProSAAS (PCSK1N).	[19]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of ProSAAS (PCSK1N).	[16]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of ProSAAS (PCSK1N).	[17]
Cocaine	DMSOX7I	Approved	Cocaine decreases the expression of ProSAAS (PCSK1N).	[18]
UNC0379	DMD1E4J	Preclinical	UNC0379 decreases the expression of ProSAAS (PCSK1N).	[20]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of ProSAAS (PCSK1N).	[21]

References

• [1] Penicisulfuranol A, a novel C-terminal inhibitor disrupting molecular chaperone function of Hsp90 independent of ATP binding domain.Biochem Pharmacol. 2019 May;163:404-415. doi: 10.1016/j.bcp.2019.03.012. Epub 2019 Mar 8.
• [2] A novel function for proSAAS as an amyloid anti-aggregant in Alzheimer's disease.J Neurochem. 2014 Feb;128(3):419-30. doi: 10.1111/jnc.12454. Epub 2013 Oct 24.
• [3] Neuropeptide PEN and Its Receptor GPR83: Distribution, Signaling, and Regulation.ACS Chem Neurosci. 2019 Apr 17;10(4):1884-1891. doi: 10.1021/acschemneuro.8b00559. Epub 2019 Feb 21.
• [4] Opioid-Induced Signaling and Antinociception Are Modulated by the Recently Deorphanized Receptor, GPR171.J Pharmacol Exp Ther. 2019 Oct;371(1):56-62. doi: 10.1124/jpet.119.259242. Epub 2019 Jul 15.
• [5] The BigLEN-GPR171 Peptide Receptor System Within the Basolateral Amygdala Regulates Anxiety-Like Behavior and Contextual Fear Conditioning.Neuropsychopharmacology. 2017 Dec;42(13):2527-2536. doi: 10.1038/npp.2017.79. Epub 2017 Apr 20.
• [6] An N-terminal fragment of ProSAAS (a granin-like neuroendocrine peptide precursor) is associated with tau inclusions in Pick's disease.Biochem Biophys Res Commun. 2003 Aug 29;308(3):646-54. doi: 10.1016/s0006-291x(03)01391-3.
• [7] The influence of socio-cultural factors on breast cancer screening behaviors in Lagos, Nigeria.Ethn Health. 2019 Jul;24(5):544-559. doi: 10.1080/13557858.2017.1348489. Epub 2017 Jul 5.
• [8] Quantitative Mass Spectrometry Reveals Food Intake-Induced Neuropeptide Level Changes in Rat Brain: Functional Assessment of Selected Neuropeptides as Feeding Regulators.Mol Cell Proteomics. 2017 Nov;16(11):1922-1937. doi: 10.1074/mcp.RA117.000057. Epub 2017 Sep 1.
• [9] Targeting the Somatostatin Receptor 2 with the Miniaturized Drug Conjugate, PEN-221: A Potent and Novel Therapeutic for the Treatment of Small Cell Lung Cancer.Mol Cancer Ther. 2019 Nov;18(11):1926-1936. doi: 10.1158/1535-7163.MCT-19-0022.
• [10] Is therapist evaluation of Social Anxiety/Avoidance traits associated with patient-reported attachment style?.Psychiatry Res. 2017 Nov;257:526-532. doi: 10.1016/j.psychres.2017.08.005. Epub 2017 Aug 10.
• [11] 'I believe high blood pressure can kill me:' using the PEN-3 Cultural Model to understand patients' perceptions of an intervention to control hypertension in Ghana.Ethn Health. 2019 Apr;24(3):257-270. doi: 10.1080/13557858.2017.1346178. Epub 2017 Jul 4.
• [12] Discovery of an SSTR2-Targeting Maytansinoid Conjugate (PEN-221) with Potent Activity in Vitro and in Vivo.J Med Chem. 2019 Mar 14;62(5):2708-2719. doi: 10.1021/acs.jmedchem.8b02036. Epub 2019 Feb 28.
• [13] Obesity and diabetes in transgenic mice expressing proSAAS.J Endocrinol. 2004 Mar;180(3):357-68. doi: 10.1677/joe.0.1800357.
• [14] Factors Affecting Self-Care Performance in Adolescents with Type I Diabetes According to the PEN-3 Cultural Model.Int J Endocrinol Metab. 2018 Sep 18;16(4):e62582. doi: 10.5812/ijem.62582. eCollection 2018 Oct.
• [15] 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.
• [16] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [17] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [18] Gene expression profile of the nucleus accumbens of human cocaine abusers: evidence for dysregulation of myelin. J Neurochem. 2004 Mar;88(5):1211-9. doi: 10.1046/j.1471-4159.2003.02247.x.
• [19] 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.
• [20] Epigenetic siRNA and chemical screens identify SETD8 inhibition as a therapeutic strategy for p53 activation in high-risk neuroblastoma. Cancer Cell. 2017 Jan 9;31(1):50-63.
• [21] Comprehensive analysis of transcriptomic changes induced by low and high doses of bisphenol A in HepG2 spheroids in vitro and rat liver in vivo. Environ Res. 2019 Jun;173:124-134. doi: 10.1016/j.envres.2019.03.035. Epub 2019 Mar 18.