Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT1HVYV4)

• DOT Name: Kinetochore protein Spc24 (SPC24)
• Synonyms: hSpc24
• Gene Name: SPC24
• Related Disease:
  Advanced cancer
  Breast cancer
  Breast carcinoma
  Hepatocellular carcinoma
  Lung cancer
  Lung carcinoma
  Lung neoplasm
  Neoplasm
  Non-small-cell lung cancer
  Thyroid cancer
  Thyroid gland carcinoma
  Thyroid tumor
  Bone osteosarcoma
  Osteosarcoma
  Thyroid gland undifferentiated (anaplastic) carcinoma
• UniProt ID: SPC24_HUMAN
• PDB ID: 2VE7; 3IZ0
• Pfam ID: PF08286
• Sequence:
  MAAFRDIEEVSQGLLSLLGANRAEAQQRRLLGRHEQVVERLLETQDGAEKQLREILTMEK
  EVAQSLLNAKEQVHQGGVELQQLEAGLQEAGEEDTRLKASLLQLTRELEELKEIEADLER
  QEKEVDEDTTVTIPSAVYVAQLYHQVSKIEWDYECEPGMVKGIHHGPSVAQPIHLDSTQL
  SRKFISDYLWSLVDTEW
• Function: Acts as a component of the essential kinetochore-associated NDC80 complex, which is required for chromosome segregation and spindle checkpoint activity. Required for kinetochore integrity and the organization of stable microtubule binding sites in the outer plate of the kinetochore. The NDC80 complex synergistically enhances the affinity of the SKA1 complex for microtubules and may allow the NDC80 complex to track depolymerizing microtubules.
• 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

15 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Breast cancer	DIS7DPX1	Strong	Biomarker	[2]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[2]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[3]
Lung cancer	DISCM4YA	Strong	Altered Expression	[1]
Lung carcinoma	DISTR26C	Strong	Altered Expression	[1]
Lung neoplasm	DISVARNB	Strong	Altered Expression	[1]
Neoplasm	DISZKGEW	Strong	Biomarker	[3]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[1]
Thyroid cancer	DIS3VLDH	moderate	Altered Expression	[3]
Thyroid gland carcinoma	DISMNGZ0	moderate	Altered Expression	[3]
Thyroid tumor	DISLVKMD	moderate	Altered Expression	[3]
Bone osteosarcoma	DIST1004	Limited	Biomarker	[2]
Osteosarcoma	DISLQ7E2	Limited	Biomarker	[2]
Thyroid gland undifferentiated (anaplastic) carcinoma	DISYBB1W	Limited	Biomarker	[2]

18 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 Kinetochore protein Spc24 (SPC24).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Kinetochore protein Spc24 (SPC24).	[5]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Kinetochore protein Spc24 (SPC24).	[6]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Kinetochore protein Spc24 (SPC24).	[7]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Kinetochore protein Spc24 (SPC24).	[8]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Kinetochore protein Spc24 (SPC24).	[9]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Kinetochore protein Spc24 (SPC24).	[9]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of Kinetochore protein Spc24 (SPC24).	[10]
Zoledronate	DMIXC7G	Approved	Zoledronate decreases the expression of Kinetochore protein Spc24 (SPC24).	[11]
Ethanol	DMDRQZU	Approved	Ethanol decreases the expression of Kinetochore protein Spc24 (SPC24).	[12]
Palbociclib	DMD7L94	Approved	Palbociclib decreases the expression of Kinetochore protein Spc24 (SPC24).	[13]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Kinetochore protein Spc24 (SPC24).	[14]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Kinetochore protein Spc24 (SPC24).	[15]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Kinetochore protein Spc24 (SPC24).	[16]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Kinetochore protein Spc24 (SPC24).	[17]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Kinetochore protein Spc24 (SPC24).	[19]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Kinetochore protein Spc24 (SPC24).	[20]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of Kinetochore protein Spc24 (SPC24).	[22]

2 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Kinetochore protein Spc24 (SPC24).	[18]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of Kinetochore protein Spc24 (SPC24).	[21]

References

• [1] A potential prognostic biomarker SPC24 promotes tumorigenesis and metastasis in lung cancer.Oncotarget. 2017 Jul 4;8(39):65469-65480. doi: 10.18632/oncotarget.18971. eCollection 2017 Sep 12.
• [2] SPC24 Regulates breast cancer progression by PI3K/AKT signaling.Gene. 2018 Oct 30;675:272-277. doi: 10.1016/j.gene.2018.07.017. Epub 2018 Jul 6.
• [3] SPC24 is critical for anaplastic thyroid cancer progression.Oncotarget. 2017 Mar 28;8(13):21884-21891. doi: 10.18632/oncotarget.15670.
• [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] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [6] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [7] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [8] 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.
• [9] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [10] Methotrexate modulates folate phenotype and inflammatory profile in EA.hy 926 cells. Eur J Pharmacol. 2014 Jun 5;732:60-7.
• [11] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [12] Chronic ethanol exposure increases goosecoid (GSC) expression in human embryonic carcinoma cell differentiation. J Appl Toxicol. 2014 Jan;34(1):66-75.
• [13] Cdk4/6 inhibition induces epithelial-mesenchymal transition and enhances invasiveness in pancreatic cancer cells. Mol Cancer Ther. 2012 Oct;11(10):2138-48. doi: 10.1158/1535-7163.MCT-12-0562. Epub 2012 Aug 6.
• [14] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [15] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [16] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [17] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [18] 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.
• [19] 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.
• [20] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [21] 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.
• [22] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.