Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT6EXJZN)

• DOT Name: Pre-mRNA-processing factor 40 homolog A (PRPF40A)
• Synonyms: Fas ligand-associated factor 1; Formin-binding protein 11; Formin-binding protein 3; Huntingtin yeast partner A; Huntingtin-interacting protein 10; HIP-10; Huntingtin-interacting protein A; Renal carcinoma antigen NY-REN-6
• Gene Name: PRPF40A
• Related Disease:
  Colon cancer
  Colon carcinoma
  Extrapulmonary tuberculosis
  Advanced cancer
  Atopic dermatitis
  Behcet disease
  Neoplasm
  Non-small-cell lung cancer
  Rheumatic heart disease
  Pancreatic cancer
  Huntington disease
  Nervous system disease
  Primary biliary cholangitis
  Rett syndrome
• UniProt ID: PR40A_HUMAN
• PDB ID: 1UZC; 1YWI; 1YWJ; 1ZR7; 2CQN; 2DYF; 2KZG; 2L5F; 2L9V; 2LKS
• Pfam ID: PF01846 ; PF00397
• Sequence:
  MRPGTGAERGGLMVSEMESHPPSQGPGDGERRLSGSSLCSGSWVSADGFLRRRPSMGHPG
  MHYAPMGMHPMGQRANMPPVPHGMMPQMMPPMGGPPMGQMPGMMSSVMPGMMMSHMSQAS
  MQPALPPGVNSMDVAAGTASGAKSMWTEHKSPDGRTYYYNTETKQSTWEKPDDLKTPAEQ
  LLSKCPWKEYKSDSGKPYYYNSQTKESRWAKPKELEDLEGYQNTIVAGSLITKSNLHAMI
  KAEESSKQEECTTTSTAPVPTTEIPTTMSTMAAAEAAAAVVAAAAAAAAAAAAANANAST
  SASNTVSGTVPVVPEPEVTSIVATVVDNENTVTISTEEQAQLTSTPAIQDQSVEVSSNTG
  EETSKQETVADFTPKKEEEESQPAKKTYTWNTKEEAKQAFKELLKEKRVPSNASWEQAMK
  MIINDPRYSALAKLSEKKQAFNAYKVQTEKEEKEEARSKYKEAKESFQRFLENHEKMTST
  TRYKKAEQMFGEMEVWNAISERDRLEIYEDVLFFLSKKEKEQAKQLRKRNWEALKNILDN
  MANVTYSTTWSEAQQYLMDNPTFAEDEELQNMDKEDALICFEEHIRALEKEEEEEKQKSL
  LRERRRQRKNRESFQIFLDELHEHGQLHSMSSWMELYPTISSDIRFTNMLGQPGSTALDL
  FKFYVEDLKARYHDEKKIIKDILKDKGFVVEVNTTFEDFVAIISSTKRSTTLDAGNIKLA
  FNSLLEKAEAREREREKEEARKMKRKESAFKSMLKQAAPPIELDAVWEDIRERFVKEPAF
  EDITLESERKRIFKDFMHVLEHECQHHHSKNKKHSKKSKKHHRKRSRSRSGSDSDDDDSH
  SKKKRQRSESRSASEHSSSAESERSYKKSKKHKKKSKKRRHKSDSPESDAEREKDKKEKD
  RESEKDRTRQRSESKHKSPKKKTGKDSGNWDTSGSELSEGELEKRRRTLLEQLDDDQ
• Function: Binds to WASL/N-WASP and suppresses its translocation from the nucleus to the cytoplasm, thereby inhibiting its cytoplasmic function. Plays a role in the regulation of cell morphology and cytoskeletal organization. Required in the control of cell shape and migration. May play a role in cytokinesis. May be involved in pre-mRNA splicing.
• Tissue Specificity: Expressed in the brain cortex (at protein level). Widely expressed.
• KEGG Pathway: Spliceosome (hsa03040)
• Reactome Pathway: mRNA Splicing - Major Pathway (R-HSA-72163)

Molecular Interaction Atlas (MIA) of This DOT

14 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Colon cancer	DISVC52G	Definitive	Genetic Variation	[1]
Colon carcinoma	DISJYKUO	Definitive	Genetic Variation	[1]
Extrapulmonary tuberculosis	DIS6KM28	Definitive	Biomarker	[2]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[3]
Atopic dermatitis	DISTCP41	Strong	Genetic Variation	[4]
Behcet disease	DISSYMBS	Strong	Biomarker	[5]
Neoplasm	DISZKGEW	Strong	Biomarker	[6]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[6]
Rheumatic heart disease	DISCI8JQ	Strong	Biomarker	[7]
Pancreatic cancer	DISJC981	moderate	Biomarker	[8]
Huntington disease	DISQPLA4	Limited	Biomarker	[9]
Nervous system disease	DISJ7GGT	Limited	Biomarker	[9]
Primary biliary cholangitis	DIS43E0O	Limited	Genetic Variation	[10]
Rett syndrome	DISGG5UV	Limited	Biomarker	[9]

5 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 Pre-mRNA-processing factor 40 homolog A (PRPF40A).	[11]
TAK-243	DM4GKV2	Phase 1	TAK-243 decreases the sumoylation of Pre-mRNA-processing factor 40 homolog A (PRPF40A).	[17]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Pre-mRNA-processing factor 40 homolog A (PRPF40A).	[18]
Coumarin	DM0N8ZM	Investigative	Coumarin affects the phosphorylation of Pre-mRNA-processing factor 40 homolog A (PRPF40A).	[18]
Hexadecanoic acid	DMWUXDZ	Investigative	Hexadecanoic acid increases the phosphorylation of Pre-mRNA-processing factor 40 homolog A (PRPF40A).	[19]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin affects the expression of Pre-mRNA-processing factor 40 homolog A (PRPF40A).	[12]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Pre-mRNA-processing factor 40 homolog A (PRPF40A).	[13]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Pre-mRNA-processing factor 40 homolog A (PRPF40A).	[14]
Selenium	DM25CGV	Approved	Selenium decreases the expression of Pre-mRNA-processing factor 40 homolog A (PRPF40A).	[15]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of Pre-mRNA-processing factor 40 homolog A (PRPF40A).	[16]
Tamibarotene	DM3G74J	Phase 3	Tamibarotene affects the expression of Pre-mRNA-processing factor 40 homolog A (PRPF40A).	[12]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of Pre-mRNA-processing factor 40 homolog A (PRPF40A).	[15]
KOJIC ACID	DMP84CS	Investigative	KOJIC ACID decreases the expression of Pre-mRNA-processing factor 40 homolog A (PRPF40A).	[20]

References

• [1] 3'-UTR and functional secretor haplotypes in mannose-binding lectin 2 are associated with increased colon cancer risk in African Americans.Cancer Res. 2012 Mar 15;72(6):1467-77. doi: 10.1158/0008-5472.CAN-11-3073. Epub 2012 Jan 26.
• [2] Mannose-binding lectin exon 1 and promoter polymorphisms in tuberculosis disease in a Mediterranean area.Int J Immunogenet. 2014 Aug;41(4):306-11. doi: 10.1111/iji.12126. Epub 2014 Jun 9.
• [3] Human PRPF40B regulates hundreds of alternative splicing targets and represses a hypoxia expression signature.RNA. 2019 Aug;25(8):905-920. doi: 10.1261/rna.069534.118. Epub 2019 May 14.
• [4] Association of Single-Nucleotide Polymorphisms of the MBL2 with Atopic Dermatitis in Korean Patients.Ann Dermatol. 2017 Oct;29(5):571-577. doi: 10.5021/ad.2017.29.5.571. Epub 2017 Aug 25.
• [5] Association of HYPA haplotype in the mannose-binding lectin gene-2 with Behet's disease.Tissue Antigens. 2005 Mar;65(3):260-5. doi: 10.1111/j.1399-0039.2005.00363.x.
• [6] COL1A1, PRPF40A, and UCP2 correlate with hypoxia markers in non-small cell lung cancer.J Cancer Res Clin Oncol. 2017 Jul;143(7):1133-1141. doi: 10.1007/s00432-017-2381-y. Epub 2017 Mar 3.
• [7] The association between mannose-binding lectin gene polymorphism and rheumatic heart disease.Hum Immunol. 2006 Dec;67(12):991-8. doi: 10.1016/j.humimm.2006.08.296. Epub 2006 Oct 9.
• [8] PRPF40A as a potential diagnostic and prognostic marker is upregulated in pancreatic cancer tissues and cell lines: an integrated bioinformatics data analysis.Onco Targets Ther. 2019 Jun 28;12:5037-5051. doi: 10.2147/OTT.S206039. eCollection 2019.
• [9] Structure of FBP11 WW1-PL ligand complex reveals the mechanism of proline-rich ligand recognition by group II/III WW domains.J Biol Chem. 2006 Dec 29;281(52):40321-9. doi: 10.1074/jbc.M609321200. Epub 2006 Oct 24.
• [10] Single nucleotide polymorphisms of the mannose-binding lectin are associated with susceptibility to primary biliary cirrhosis.J Autoimmun. 2001 Nov;17(3):251-7. doi: 10.1006/jaut.2001.0538.
• [11] 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.
• [12] Differential modulation of PI3-kinase/Akt pathway during all-trans retinoic acid- and Am80-induced HL-60 cell differentiation revealed by DNA microarray analysis. Biochem Pharmacol. 2004 Dec 1;68(11):2177-86.
• [13] 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.
• [14] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [15] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [16] Gene expression in endometrial cancer cells (Ishikawa) after short time high dose exposure to progesterone. Steroids. 2008 Jan;73(1):116-28.
• [17] 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.
• [18] 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.
• [19] Functional lipidomics: Palmitic acid impairs hepatocellular carcinoma development by modulating membrane fluidity and glucose metabolism. Hepatology. 2017 Aug;66(2):432-448. doi: 10.1002/hep.29033. Epub 2017 Jun 16.
• [20] Toxicogenomics of kojic acid on gene expression profiling of a375 human malignant melanoma cells. Biol Pharm Bull. 2006 Apr;29(4):655-69.