Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTNW2U4Y)

• DOT Name: Splicing factor 3B subunit 2 (SF3B2)
• Synonyms: Pre-mRNA-splicing factor SF3b 145 kDa subunit; SF3b145; Spliceosome-associated protein 145; SAP 145
• Gene Name: SF3B2
• Related Disease:
  Acute myelogenous leukaemia
  Advanced cancer
  Breast neoplasm
  Cutaneous melanoma
  Hepatocellular carcinoma
  Medulloblastoma
  Myelodysplastic syndrome
  Neoplasm
  Pancreatic adenocarcinoma
  Prostate cancer
  Prostate carcinoma
  Renal cell carcinoma
  Small lymphocytic lymphoma
• UniProt ID: SF3B2_HUMAN
• PDB ID: 2DO5; 5Z56; 5Z57; 5Z58; 6AH0; 6AHD; 6FF4; 6FF7; 6QX9; 6Y50; 6Y53; 6Y5Q; 7ABG; 7ABH; 7ABI; 7DVQ; 7EVO; 7ONB; 7Q3L; 7Q4O; 7Q4P; 7QTT; 7VPX; 8CH6; 8HK1
• Pfam ID: PF04037 ; PF04046 ; PF02037
• Sequence:
  MATEHPEPPKAELQLPPPPPPGHYGAWAAQELQAKLAEIGAPIQGNREELVERLQSYTRQ
  TGIVLNRPVLRGEDGDKAAPPPMSAQLPGIPMPPPPLGLPPLQPPPPPPPPPPGLGLGFP
  MAHPPNLGPPPPLRVGEPVALSEEERLKLAQQQAALLMQQEERAKQQGDHSLKEHELLEQ
  QKRAAVLLEQERQQEIAKMGTPVPRPPQDMGQIGVRTPLGPRVAAPVGPVGPTPTVLPMG
  APVPRPRGPPPPPGDENREMDDPSVGPKIPQALEKILQLKESRQEEMNSQQEEEEMETDA
  RSSLGQSASETEEDTVSVSKKEKNRKRRNRKKKKKPQRVRGVSSESSGDREKDSTRSRGS
  DSPAADVEIEYVTEEPEIYEPNFIFFKRIFEAFKLTDDVKKEKEKEPEKLDKLENSAAPK
  KKGFEEEHKDSDDDSSDDEQEKKPEAPKLSKKKLRRMNRFTVAELKQLVARPDVVEMHDV
  TAQDPKLLVHLKATRNSVPVPRHWCFKRKYLQGKRGIEKPPFELPDFIKRTGIQEMREAL
  QEKEEQKTMKSKMREKVRPKMGKIDIDYQKLHDAFFKWQTKPKLTIHGDLYYEGKEFETR
  LKEKKPGDLSDELRISLGMPVGPNAHKVPPPWLIAMQRYGPPPSYPNLKIPGLNSPIPES
  CSFGYHAGGWGKPPVDETGKPLYGDVFGTNAAEFQTKTEEEEIDRTPWGELEPSDEESSE
  EEEEEESDEDKPDETGFITPADSGLITPGGFSSVPAGMETPELIELRKKKIEEAMDGSET
  PQLFTVLPEKRTATVGGAMMGSTHIYDMSTVMSRKGPAPELQGVEVALAPEELELDPMAM
  TQKYEEHVREQQAQVEKEDFSDMVAEHAAKQKQKKRKAQPQDSRGGSKKYKEFKF
• Function: Component of the 17S U2 SnRNP complex of the spliceosome, a large ribonucleoprotein complex that removes introns from transcribed pre-mRNAs. The 17S U2 SnRNP complex (1) directly participates in early spliceosome assembly and (2) mediates recognition of the intron branch site during pre-mRNA splicing by promoting the selection of the pre-mRNA branch-site adenosine, the nucleophile for the first step of splicing. Within the 17S U2 SnRNP complex, SF3B2 is part of the SF3B subcomplex, which is required for 'A' complex assembly formed by the stable binding of U2 snRNP to the branchpoint sequence in pre-mRNA. Sequence independent binding of SF3A and SF3B subcomplexes upstream of the branch site is essential, it may anchor U2 snRNP to the pre-mRNA. May also be involved in the assembly of the 'E' complex. Also acts as a component of the minor spliceosome, which is involved in the splicing of U12-type introns in pre-mRNAs.
• KEGG Pathway: Spliceosome (hsa03040)
• Reactome Pathway:
  mRNA Splicing - Minor Pathway (R-HSA-72165)
  mRNA Splicing - Major Pathway (R-HSA-72163)

Molecular Interaction Atlas (MIA) of This DOT

13 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute myelogenous leukaemia	DISCSPTN	Strong	Genetic Variation	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Breast neoplasm	DISNGJLM	Strong	Genetic Variation	[1]
Cutaneous melanoma	DIS3MMH9	Strong	Genetic Variation	[1]
Hepatocellular carcinoma	DIS0J828	Strong	Genetic Variation	[1]
Medulloblastoma	DISZD2ZL	Strong	Genetic Variation	[1]
Myelodysplastic syndrome	DISYHNUI	Strong	Genetic Variation	[1]
Neoplasm	DISZKGEW	Strong	Altered Expression	[2]
Pancreatic adenocarcinoma	DISKHX7S	Strong	Genetic Variation	[1]
Prostate cancer	DISF190Y	Strong	Altered Expression	[2]
Prostate carcinoma	DISMJPLE	Strong	Altered Expression	[2]
Renal cell carcinoma	DISQZ2X8	Strong	Genetic Variation	[1]
Small lymphocytic lymphoma	DIS30POX	Strong	Genetic Variation	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Splicing factor 3B subunit 2 (SF3B2).	[3]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Splicing factor 3B subunit 2 (SF3B2).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Splicing factor 3B subunit 2 (SF3B2).	[5]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Splicing factor 3B subunit 2 (SF3B2).	[6]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Splicing factor 3B subunit 2 (SF3B2).	[7]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Splicing factor 3B subunit 2 (SF3B2).	[10]

5 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 Splicing factor 3B subunit 2 (SF3B2).	[8]
TAK-243	DM4GKV2	Phase 1	TAK-243 decreases the sumoylation of Splicing factor 3B subunit 2 (SF3B2).	[9]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of Splicing factor 3B subunit 2 (SF3B2).	[11]
Glyphosate	DM0AFY7	Investigative	Glyphosate affects the methylation of Splicing factor 3B subunit 2 (SF3B2).	[12]
Hexadecanoic acid	DMWUXDZ	Investigative	Hexadecanoic acid increases the phosphorylation of Splicing factor 3B subunit 2 (SF3B2).	[13]

References

• [1] Identifying recurrent mutations in cancer reveals widespread lineage diversity and mutational specificity.Nat Biotechnol. 2016 Feb;34(2):155-63. doi: 10.1038/nbt.3391. Epub 2015 Nov 30.
• [2] SF3B2-Mediated RNA Splicing Drives Human Prostate Cancer Progression.Cancer Res. 2019 Oct 15;79(20):5204-5217. doi: 10.1158/0008-5472.CAN-18-3965. Epub 2019 Aug 20.
• [3] 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.
• [4] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [5] 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.
• [6] 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.
• [7] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [8] 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.
• [9] 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.
• [10] Environmental pollutant induced cellular injury is reflected in exosomes from placental explants. Placenta. 2020 Jan 1;89:42-49. doi: 10.1016/j.placenta.2019.10.008. Epub 2019 Oct 17.
• [11] 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.
• [12] Association of Glyphosate Exposure with Blood DNA Methylation in a Cross-Sectional Study of Postmenopausal Women. Environ Health Perspect. 2022 Apr;130(4):47001. doi: 10.1289/EHP10174. Epub 2022 Apr 4.
• [13] 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.