Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTTTG9PG)

• DOT Name: Pappalysin-1 (PAPPA)
• Synonyms: EC 3.4.24.79; Insulin-like growth factor-dependent IGF-binding protein 4 protease; IGF-dependent IGFBP-4 protease; IGFBP-4ase; Pregnancy-associated plasma protein A; PAPP-A
• Gene Name: PAPPA
• Related Disease:
  Non-insulin dependent diabetes
  Non-small-cell lung cancer
  Acute coronary syndrome
  Acute myocardial infarction
  Advanced cancer
  Arteriosclerosis
  Atherosclerosis
  Breast cancer
  Breast carcinoma
  Cardiac disease
  Cardiac failure
  Chronic kidney disease
  Chronic renal failure
  Congestive heart failure
  Coronary atherosclerosis
  Coronary heart disease
  End-stage renal disease
  Epithelial ovarian cancer
  Ewing sarcoma
  Fatty liver disease
  Fetal growth restriction
  Hidradenitis suppurativa
  HIV infectious disease
  Hypertension, pregnancy-induced
  Lung cancer
  Lung carcinoma
  Myocardial infarction
  Neoplasm
  Non-alcoholic fatty liver disease
  Ovarian cancer
  Ovarian neoplasm
  Polycystic ovarian syndrome
  Systemic lupus erythematosus
  Cardiovascular disease
  Eclampsia
  Endometriosis
  Female infertility
  Melanoma
  Myocardial ischemia
  Type-1/2 diabetes
  Ankylosing spondylitis
  Chromosomal disorder
  Clear cell renal carcinoma
  Pyoderma gangrenosum
• UniProt ID: PAPP1_HUMAN
• PDB ID: 7UFG; 7Y5N; 7Y5Q; 8A7D; 8A7E; 8D8O; 8HGG; 8HGH
• EC Number: 3.4.24.79
• Pfam ID: PF13385 ; PF05572 ; PF00084
• Sequence:
  MRLWSWVLHLGLLSAALGCGLAERPRRARRDPRAGRPPRPAAGPATCATRAARGRRASPP
  PPPPPGGAWEAVRVPRRRQQREARGATEEPSPPSRALYFSGRGEQLRLRADLELPRDAFT
  LQVWLRAEGGQRSPAVITGLYDKCSYISRDRGWVVGIHTISDQDNKDPRYFFSLKTDRAR
  QVTTINAHRSYLPGQWVYLAATYDGQFMKLYVNGAQVATSGEQVGGIFSPLTQKCKVLML
  GGSALNHNYRGYIEHFSLWKVARTQREILSDMETHGAHTALPQLLLQENWDNVKHAWSPM
  KDGSSPKVEFSNAHGFLLDTSLEPPLCGQTLCDNTEVIASYNQLSSFRQPKVVRYRVVNL
  YEDDHKNPTVTREQVDFQHHQLAEAFKQYNISWELDVLEVSNSSLRRRLILANCDISKIG
  DENCDPECNHTLTGHDGGDCRHLRHPAFVKKQHNGVCDMDCNYERFNFDGGECCDPEITN
  VTQTCFDPDSPHRAYLDVNELKNILKLDGSTHLNIFFAKSSEEELAGVATWPWDKEALMH
  LGGIVLNPSFYGMPGHTHTMIHEIGHSLGLYHVFRGISEIQSCSDPCMETEPSFETGDLC
  NDTNPAPKHKSCGDPGPGNDTCGFHSFFNTPYNNFMSYADDDCTDSFTPNQVARMHCYLD
  LVYQGWQPSRKPAPVALAPQVLGHTTDSVTLEWFPPIDGHFFERELGSACHLCLEGRILV
  QYASNASSPMPCSPSGHWSPREAEGHPDVEQPCKSSVRTWSPNSAVNPHTVPPACPEPQG
  CYLELEFLYPLVPESLTIWVTFVSTDWDSSGAVNDIKLLAVSGKNISLGPQNVFCDVPLT
  IRLWDVGEEVYGIQIYTLDEHLEIDAAMLTSTADTPLCLQCKPLKYKVVRDPPLQMDVAS
  ILHLNRKFVDMDLNLGSVYQYWVITISGTEESEPSPAVTYIHGSGYCGDGIIQKDQGEQC
  DDMNKINGDGCSLFCRQEVSFNCIDEPSRCYFHDGDGVCEEFEQKTSIKDCGVYTPQGFL
  DQWASNASVSHQDQQCPGWVIIGQPAASQVCRTKVIDLSEGISQHAWYPCTISYPYSQLA
  QTTFWLRAYFSQPMVAAAVIVHLVTDGTYYGDQKQETISVQLLDTKDQSHDLGLHVLSCR
  NNPLIIPVVHDLSQPFYHSQAVRVSFSSPLVAISGVALRSFDNFDPVTLSSCQRGETYSP
  AEQSCVHFACEKTDCPELAVENASLNCSSSDRYHGAQCTVSCRTGYVLQIRRDDELIKSQ
  TGPSVTVTCTEGKWNKQVACEPVDCSIPDHHQVYAASFSCPEGTTFGSQCSFQCRHPAQL
  KGNNSLLTCMEDGLWSFPEALCELMCLAPPPVPNADLQTARCRENKHKVGSFCKYKCKPG
  YHVPGSSRKSKKRAFKTQCTQDGSWQEGACVPVTCDPPPPKFHGLYQCTNGFQFNSECRI
  KCEDSDASQGLGSNVIHCRKDGTWNGSFHVCQEMQGQCSVPNELNSNLKLQCPDGYAIGS
  ECATSCLDHNSESIILPMNVTVRDIPHWLNPTRVERVVCTAGLKWYPHPALIHCVKGCEP
  FMGDNYCDAINNRAFCNYDGGDCCTSTVKTKKVTPFPMSCDLQGDCACRDPQAQEHSRKD
  LRGYSHG
• Function: Metalloproteinase which specifically cleaves IGFBP-4 and IGFBP-5, resulting in release of bound IGF. Cleavage of IGFBP-4 is dramatically enhanced by the presence of IGF, whereas cleavage of IGFBP-5 is slightly inhibited by the presence of IGF.
• Tissue Specificity: High levels in placenta and pregnancy serum. In placenta, expressed in X cells in septa and anchoring villi, and in syncytiotrophoblasts in the chorionic villi. Lower levels are found in a variety of other tissues including kidney, myometrium, endometrium, ovaries, breast, prostate, bone marrow, colon, fibroblasts and osteoblasts.
• Reactome Pathway: Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs) (R-HSA-381426)
• BioCyc Pathway: MetaCyc:ENSG00000119398-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

44 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Non-insulin dependent diabetes	DISK1O5Z	Definitive	Altered Expression	[1]
Non-small-cell lung cancer	DIS5Y6R9	Definitive	Genetic Variation	[2]
Acute coronary syndrome	DIS7DYEW	Strong	Biomarker	[3]
Acute myocardial infarction	DISE3HTG	Strong	Biomarker	[4]
Advanced cancer	DISAT1Z9	Strong	Genetic Variation	[5]
Arteriosclerosis	DISK5QGC	Strong	Biomarker	[6]
Atherosclerosis	DISMN9J3	Strong	Biomarker	[6]
Breast cancer	DIS7DPX1	Strong	Biomarker	[7]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[7]
Cardiac disease	DISVO1I5	Strong	Altered Expression	[8]
Cardiac failure	DISDC067	Strong	Genetic Variation	[9]
Chronic kidney disease	DISW82R7	Strong	Altered Expression	[10]
Chronic renal failure	DISGG7K6	Strong	Biomarker	[11]
Congestive heart failure	DIS32MEA	Strong	Genetic Variation	[9]
Coronary atherosclerosis	DISKNDYU	Strong	Genetic Variation	[12]
Coronary heart disease	DIS5OIP1	Strong	Genetic Variation	[12]
End-stage renal disease	DISXA7GG	Strong	Biomarker	[11]
Epithelial ovarian cancer	DIS56MH2	Strong	Biomarker	[13]
Ewing sarcoma	DISQYLV3	Strong	Biomarker	[14]
Fatty liver disease	DIS485QZ	Strong	Biomarker	[15]
Fetal growth restriction	DIS5WEJ5	Strong	Altered Expression	[16]
Hidradenitis suppurativa	DIS3ZNAK	Strong	Genetic Variation	[17]
HIV infectious disease	DISO97HC	Strong	Biomarker	[6]
Hypertension, pregnancy-induced	DISHNU25	Strong	Biomarker	[18]
Lung cancer	DISCM4YA	Strong	Biomarker	[19]
Lung carcinoma	DISTR26C	Strong	Biomarker	[19]
Myocardial infarction	DIS655KI	Strong	Genetic Variation	[20]
Neoplasm	DISZKGEW	Strong	Biomarker	[14]
Non-alcoholic fatty liver disease	DISDG1NL	Strong	Biomarker	[15]
Ovarian cancer	DISZJHAP	Strong	Biomarker	[13]
Ovarian neoplasm	DISEAFTY	Strong	Biomarker	[13]
Polycystic ovarian syndrome	DISZ2BNG	Strong	Altered Expression	[21]
Systemic lupus erythematosus	DISI1SZ7	Strong	Altered Expression	[22]
Cardiovascular disease	DIS2IQDX	moderate	Biomarker	[11]
Eclampsia	DISWPO8U	moderate	Genetic Variation	[23]
Endometriosis	DISX1AG8	moderate	Genetic Variation	[24]
Female infertility	DIS9GNYZ	moderate	Biomarker	[25]
Melanoma	DIS1RRCY	moderate	Biomarker	[26]
Myocardial ischemia	DISFTVXF	moderate	Genetic Variation	[27]
Type-1/2 diabetes	DISIUHAP	moderate	Biomarker	[27]
Ankylosing spondylitis	DISRC6IR	Limited	Biomarker	[28]
Chromosomal disorder	DISM5BB5	Limited	Genetic Variation	[29]
Clear cell renal carcinoma	DISBXRFJ	Limited	Biomarker	[30]
Pyoderma gangrenosum	DIS8QVTT	Limited	Biomarker	[31]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
PEITC	DMOMN31	Phase 2	Pappalysin-1 (PAPPA) affects the binding of PEITC.	[59]

25 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 Pappalysin-1 (PAPPA).	[32]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Pappalysin-1 (PAPPA).	[33]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Pappalysin-1 (PAPPA).	[34]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Pappalysin-1 (PAPPA).	[35]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Pappalysin-1 (PAPPA).	[36]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Pappalysin-1 (PAPPA).	[37]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Pappalysin-1 (PAPPA).	[38]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Pappalysin-1 (PAPPA).	[39]
Zoledronate	DMIXC7G	Approved	Zoledronate decreases the expression of Pappalysin-1 (PAPPA).	[40]
Progesterone	DMUY35B	Approved	Progesterone decreases the expression of Pappalysin-1 (PAPPA).	[41]
Dexamethasone	DMMWZET	Approved	Dexamethasone decreases the expression of Pappalysin-1 (PAPPA).	[42]
Troglitazone	DM3VFPD	Approved	Troglitazone increases the expression of Pappalysin-1 (PAPPA).	[43]
Gemcitabine	DMSE3I7	Approved	Gemcitabine decreases the expression of Pappalysin-1 (PAPPA).	[44]
Testosterone Undecanoate	DMZO10Y	Approved	Testosterone Undecanoate decreases the expression of Pappalysin-1 (PAPPA).	[45]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Pappalysin-1 (PAPPA).	[46]
Resveratrol	DM3RWXL	Phase 3	Resveratrol decreases the expression of Pappalysin-1 (PAPPA).	[47]
GSK2110183	DMZHB37	Phase 2	GSK2110183 increases the expression of Pappalysin-1 (PAPPA).	[48]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Pappalysin-1 (PAPPA).	[50]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Pappalysin-1 (PAPPA).	[51]
Geldanamycin	DMS7TC5	Discontinued in Phase 2	Geldanamycin increases the expression of Pappalysin-1 (PAPPA).	[52]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Pappalysin-1 (PAPPA).	[54]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Pappalysin-1 (PAPPA).	[55]
Manganese	DMKT129	Investigative	Manganese increases the expression of Pappalysin-1 (PAPPA).	[56]
Cycloheximide	DMGDA3C	Investigative	Cycloheximide increases the expression of Pappalysin-1 (PAPPA).	[57]
Microcystin-LR	DMTMLRN	Investigative	Microcystin-LR increases the expression of Pappalysin-1 (PAPPA).	[58]

2 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 decreases the methylation of Pappalysin-1 (PAPPA).	[49]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Pappalysin-1 (PAPPA).	[53]

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