Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTI0JNTM)

• DOT Name: Protein Spindly (SPDL1)
• Synonyms: hSpindly; Arsenite-related gene 1 protein; Coiled-coil domain-containing protein 99; Rhabdomyosarcoma antigen MU-RMS-40.4A; Spindle apparatus coiled-coil domain-containing protein 1
• Gene Name: SPDL1
• Related Disease: Microcephaly
• UniProt ID: SPDLY_HUMAN
• PDB ID: 8ARF
• Sequence:
  MEADIITNLRCRLKEAEEERLKAAQYGLQLVESQNELQNQLDKCRNEMMTMTESYEQEKY
  TLQREVELKSRMLESLSCECEAIKQQQKMHLEKLEEQLSRSHGQEVNELKTKIEKLKVEL
  DEARLSEKQLKHQVDHQKELLSCKSEELRVMSERVQESMSSEMLALQIELTEMESMKTTL
  KEEVNELQYRQEQLELLITNLMRQVDRLKEEKEEREKEAVSYYNALEKARVANQDLQVQL
  DQALQQALDPNSKGNSLFAEVEDRRAAMERQLISMKVKYQSLKKQNVFNREQMQRMKLQI
  ATLLQMKGSQTEFEQQERLLAMLEQKNGEIKHLLGEIRNLEKFKNLYDSMESKPSVDSGT
  LEDNTYYTDLLQMKLDNLNKEIESTKGELSIQRMKALFESQRALDIERKLFANERCLQLS
  ESENMKLRAKLDELKLKYEPEETVEVPVLKKRREVLPVDITTAKDACVNNSALGGEVYRL
  PPQKEETQSCPNSLEDNNLQLEKSVSIYTPVVSLSPHKNLPVDMQLKKEKKCVKLIGVPA
  DAEALSERSGNTPNSPRLAAESKLQTEVKEGKETSSKLEKETCKKLHPILYVSSKSTPET
  QCPQQ
• Function: Required for the localization of dynein and dynactin to the mitotic kintochore. Dynein is believed to control the initial lateral interaction between the kinetochore and spindle microtubules and to facilitate the subsequent formation of end-on kinetochore-microtubule attachments mediated by the NDC80 complex. Also required for correct spindle orientation. Does not appear to be required for the removal of spindle assembly checkpoint (SAC) proteins from the kinetochore upon bipolar spindle attachment. Acts as an adapter protein linking the dynein motor complex to various cargos and converts dynein from a non-processive to a highly processive motor in the presence of dynactin. Facilitates the interaction between dynein and dynactin and activates dynein processivity (the ability to move along a microtubule for a long distance without falling off the track). Plays a role in cell migration.
• Reactome Pathway:
  Separation of Sister Chromatids (R-HSA-2467813)
  Resolution of Sister Chromatid Cohesion (R-HSA-2500257)
  RHO GTPases Activate Formins (R-HSA-5663220)
  Mitotic Prometaphase (R-HSA-68877)
  EML4 and NUDC in mitotic spindle formation (R-HSA-9648025)
  Amplification of signal from unattached kinetochores via a MAD2 inhibitory signal (R-HSA-141444)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Microcephaly	DIS2GRD8	Limited	Autosomal recessive	[1]

23 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 Protein Spindly (SPDL1).	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Protein Spindly (SPDL1).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Protein Spindly (SPDL1).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Protein Spindly (SPDL1).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Protein Spindly (SPDL1).	[6]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Protein Spindly (SPDL1).	[7]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Protein Spindly (SPDL1).	[8]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Protein Spindly (SPDL1).	[9]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Protein Spindly (SPDL1).	[10]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Protein Spindly (SPDL1).	[11]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Protein Spindly (SPDL1).	[12]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Protein Spindly (SPDL1).	[12]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Protein Spindly (SPDL1).	[11]
Azathioprine	DMMZSXQ	Approved	Azathioprine decreases the expression of Protein Spindly (SPDL1).	[13]
Piroxicam	DMTK234	Approved	Piroxicam increases the expression of Protein Spindly (SPDL1).	[14]
Lucanthone	DMZLBUO	Approved	Lucanthone decreases the expression of Protein Spindly (SPDL1).	[15]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Protein Spindly (SPDL1).	[16]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Protein Spindly (SPDL1).	[17]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Protein Spindly (SPDL1).	[18]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Protein Spindly (SPDL1).	[19]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Protein Spindly (SPDL1).	[20]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of Protein Spindly (SPDL1).	[8]
methyl p-hydroxybenzoate	DMO58UW	Investigative	methyl p-hydroxybenzoate decreases the expression of Protein Spindly (SPDL1).	[21]

References

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• [2] 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.
• [3] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [4] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [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] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [7] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [8] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [9] 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.
• [10] 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.
• [11] Time series analysis of oxidative stress response patterns in HepG2: a toxicogenomics approach. Toxicology. 2013 Apr 5;306:24-34.
• [12] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [13] A transcriptomics-based in vitro assay for predicting chemical genotoxicity in vivo. Carcinogenesis. 2012 Jul;33(7):1421-9.
• [14] Apoptosis induced by piroxicam plus cisplatin combined treatment is triggered by p21 in mesothelioma. PLoS One. 2011;6(8):e23569.
• [15] Lucanthone is a novel inhibitor of autophagy that induces cathepsin D-mediated apoptosis. J Biol Chem. 2011 Feb 25;286(8):6602-13.
• [16] Benzo[a]pyrene-induced changes in microRNA-mRNA networks. Chem Res Toxicol. 2012 Apr 16;25(4):838-49.
• [17] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [18] 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.
• [19] Bisphenol A and bisphenol S induce distinct transcriptional profiles in differentiating human primary preadipocytes. PLoS One. 2016 Sep 29;11(9):e0163318.
• [20] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [21] Transcriptome dynamics of alternative splicing events revealed early phase of apoptosis induced by methylparaben in H1299 human lung carcinoma cells. Arch Toxicol. 2020 Jan;94(1):127-140. doi: 10.1007/s00204-019-02629-w. Epub 2019 Nov 20.