Details of Drug Off-Target (DOT)

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

• DOT Name: La-related protein 7 (LARP7)
• Synonyms: La ribonucleoprotein domain family member 7; hLARP7; P-TEFb-interaction protein for 7SK stability; PIP7S
• Gene Name: LARP7
• Related Disease:
  Microcephalic primordial dwarfism, Alazami type
  Thyroid gland papillary carcinoma
  Intellectual disability
  Isolated growth hormone deficiency type IA
  Seckel syndrome
  Thyroid tumor
  Trichohepatoenteric syndrome
  Advanced cancer
  Neoplasm
  Breast cancer
  Breast carcinoma
  Gastric cancer
  Stomach cancer
• UniProt ID: LARP7_HUMAN
• PDB ID: 4WKR; 5KNW; 6D12; 7SLP; 7SLQ
• Pfam ID: PF05383 ; PF00076 ; PF08777
• Sequence:
  METESGNQEKVMEEESTEKKKEVEKKKRSRVKQVLADIAKQVDFWFGDANLHKDRFLREQ
  IEKSRDGYVDISLLVSFNKMKKLTTDGKLIARALRSSAVVELDLEGTRIRRKKPLGERPK
  DEDERTVYVELLPKNVNHSWIERVFGKCGNVVYISIPHYKSTGDPKGFAFVEFETKEQAA
  KAIEFLNNPPEEAPRKPGIFPKTVKNKPIPALRVVEEKKKKKKKKGRMKKEDNIQAKEEN
  MDTSNTSISKMKRSRPTSEGSDIESTEPQKQCSKKKKKRDRVEASSLPEVRTGKRKRSSS
  EDAESLAPRSKVKKIIQKDIIKEASEASKENRDIEISTEEEKDTGDLKDSSLLKTKRKHK
  KKHKERHKMGEEVIPLRVLSKSEWMDLKKEYLALQKASMASLKKTISQIKSESEMETDSG
  VPQNTGMKNEKTANREECRTQEKVNATGPQFVSGVIVKIISTEPLPGRKQVRDTLAAISE
  VLYVDLLEGDTECHARFKTPEDAQAVINAYTEINKKHCWKLEILSGDHEQRYWQKILVDR
  QAKLNQPREKKRGTEKLITKAEKIRLAKTQQASKHIRFSEYD
• Function: RNA-binding protein that specifically binds distinct small nuclear RNA (snRNAs) and regulates their processing and function. Specifically binds the 7SK snRNA (7SK RNA) and acts as a core component of the 7SK ribonucleoprotein (RNP) complex, thereby acting as a negative regulator of transcription elongation by RNA polymerase II. The 7SK RNP complex sequesters the positive transcription elongation factor b (P-TEFb) in a large inactive 7SK RNP complex preventing RNA polymerase II phosphorylation and subsequent transcriptional elongation. The 7SK RNP complex also promotes snRNA gene transcription by RNA polymerase II via interaction with the little elongation complex (LEC). LARP7 specifically binds to the highly conserved 3'-terminal U-rich stretch of 7SK RNA; on stimulation, remains associated with 7SK RNA, whereas P-TEFb is released from the complex. LARP7 also acts as a regulator of mRNA splicing fidelity by promoting U6 snRNA processing. Specifically binds U6 snRNAs and associates with a subset of box C/D RNP complexes: promotes U6 snRNA 2'-O-methylation by facilitating U6 snRNA loading into box C/D RNP complexes. U6 snRNA 2'-O-methylation is required for mRNA splicing fidelity. Binds U6 snRNAs with a 5'-CAGGG-3' sequence motif. U6 snRNA processing is required for spermatogenesis.

Molecular Interaction Atlas (MIA) of This DOT

13 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Microcephalic primordial dwarfism, Alazami type	DISVNPZ3	Definitive	Autosomal recessive	[1]
Thyroid gland papillary carcinoma	DIS48YMM	Definitive	Altered Expression	[2]
Intellectual disability	DISMBNXP	Strong	Genetic Variation	[3]
Isolated growth hormone deficiency type IA	DISLPIAM	Strong	Biomarker	[4]
Seckel syndrome	DISEVUBA	Strong	Genetic Variation	[5]
Thyroid tumor	DISLVKMD	Strong	Biomarker	[6]
Trichohepatoenteric syndrome	DISL3ODF	Strong	Genetic Variation	[1]
Advanced cancer	DISAT1Z9	moderate	Biomarker	[7]
Neoplasm	DISZKGEW	moderate	Biomarker	[6]
Breast cancer	DIS7DPX1	Limited	Altered Expression	[8]
Breast carcinoma	DIS2UE88	Limited	Altered Expression	[8]
Gastric cancer	DISXGOUK	Limited	Biomarker	[6]
Stomach cancer	DISKIJSX	Limited	Biomarker	[6]

3 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 La-related protein 7 (LARP7).	[9]
TAK-243	DM4GKV2	Phase 1	TAK-243 decreases the sumoylation of La-related protein 7 (LARP7).	[21]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of La-related protein 7 (LARP7).	[23]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of La-related protein 7 (LARP7).	[10]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of La-related protein 7 (LARP7).	[11]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of La-related protein 7 (LARP7).	[12]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of La-related protein 7 (LARP7).	[13]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of La-related protein 7 (LARP7).	[14]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of La-related protein 7 (LARP7).	[15]
Decitabine	DMQL8XJ	Approved	Decitabine increases the expression of La-related protein 7 (LARP7).	[16]
Ethanol	DMDRQZU	Approved	Ethanol decreases the expression of La-related protein 7 (LARP7).	[17]
Clozapine	DMFC71L	Approved	Clozapine increases the expression of La-related protein 7 (LARP7).	[18]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of La-related protein 7 (LARP7).	[19]
Tanespimycin	DMNLQHK	Phase 2	Tanespimycin increases the expression of La-related protein 7 (LARP7).	[20]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of La-related protein 7 (LARP7).	[22]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of La-related protein 7 (LARP7).	[24]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of La-related protein 7 (LARP7).	[25]
KOJIC ACID	DMP84CS	Investigative	KOJIC ACID decreases the expression of La-related protein 7 (LARP7).	[26]

References

• [1] Broadening the phenotypic spectrum of pathogenic LARP7 variants: two cases with intellectual disability, variable growth retardation and distinct facial features. J Hum Genet. 2016 Mar;61(3):229-33. doi: 10.1038/jhg.2015.134. Epub 2015 Nov 26.
• [2] LARP7 in papillary thyroid carcinoma induces NIS expression through suppression of the SHH signaling pathway.Mol Med Rep. 2018 Jun;17(6):7521-7528. doi: 10.3892/mmr.2018.8856. Epub 2018 Apr 5.
• [3] de novo MEPCE nonsense variant associated with a neurodevelopmental disorder causes disintegration of 7SK snRNP and enhanced RNA polymerase II activation.Sci Rep. 2019 Aug 29;9(1):12516. doi: 10.1038/s41598-019-49032-0.
• [4] Compound heterozygous variants in the LARP7 gene as a cause of Alazami syndrome in a Caucasian female with significant failure to thrive, short stature, and developmental disability.Am J Med Genet A. 2016 Jan;170A(1):217-9. doi: 10.1002/ajmg.a.37396. Epub 2015 Sep 16.
• [5] LARP7 variants and further delineation of the Alazami syndrome phenotypic spectrum among primordial dwarfisms: 2 sisters.Eur J Med Genet. 2019 Mar;62(3):161-166. doi: 10.1016/j.ejmg.2018.07.003. Epub 2018 Jul 10.
• [6] Alazami syndrome: the first case of papillary thyroid carcinoma.J Hum Genet. 2020 Jan;65(2):133-141. doi: 10.1038/s10038-019-0682-5. Epub 2019 Oct 28.
• [7] The La-Related Proteins, a Family with Connections to Cancer.Biomolecules. 2015 Oct 16;5(4):2701-22. doi: 10.3390/biom5042701.
• [8] LARP7 suppresses P-TEFb activity to inhibit breast cancer progression and metastasis.Elife. 2014 Jul 22;3:e02907. doi: 10.7554/eLife.02907.
• [9] 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.
• [10] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [11] 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.
• [12] 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.
• [13] 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.
• [14] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [15] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [16] The DNA methyltransferase inhibitors azacitidine, decitabine and zebularine exert differential effects on cancer gene expression in acute myeloid leukemia cells. Leukemia. 2009 Jun;23(6):1019-28.
• [17] Gene expression signatures after ethanol exposure in differentiating embryoid bodies. Toxicol In Vitro. 2018 Feb;46:66-76.
• [18] Cannabidiol Displays Proteomic Similarities to Antipsychotics in Cuprizone-Exposed Human Oligodendrocytic Cell Line MO3.13. Front Mol Neurosci. 2021 May 28;14:673144. doi: 10.3389/fnmol.2021.673144. eCollection 2021.
• [19] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [20] Impact of Heat Shock Protein 90 Inhibition on the Proteomic Profile of Lung Adenocarcinoma as Measured by Two-Dimensional Electrophoresis Coupled with Mass Spectrometry. Cells. 2019 Jul 31;8(8):806. doi: 10.3390/cells8080806.
• [21] 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.
• [22] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [23] 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.
• [24] 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.
• [25] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [26] Toxicogenomics of kojic acid on gene expression profiling of a375 human malignant melanoma cells. Biol Pharm Bull. 2006 Apr;29(4):655-69.