Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTG8RV8E)

DOT Name	Insulinoma-associated protein 1 (INSM1)
Synonyms	Zinc finger protein IA-1
Gene Name	INSM1
Related Disease	Pancreatic ductal carcinoma ( ) Acinar cell carcinoma ( ) Chondrosarcoma ( ) Chordoma ( ) Embryonal neoplasm ( ) Ewing sarcoma ( ) Herpes simplex infection ( ) Lung cancer ( ) Lung carcinoma ( ) Medullary thyroid gland carcinoma ( ) Medulloblastoma ( ) Pancreatic neuroendocrine tumor ( ) Paraganglioma ( ) Pineoblastoma ( ) Prostate carcinoma ( ) Squamous cell carcinoma ( ) Adult glioblastoma ( ) Advanced cancer ( ) Breast carcinoma ( ) Carcinoma ( ) Ganglioneuroblastoma ( ) Glioblastoma multiforme ( ) Metastatic malignant neoplasm ( ) Neuroblastic tumor ( ) Neuroendocrine cancer ( ) Primitive neuroectodermal tumor ( ) Prostate adenocarcinoma ( ) Retinoblastoma ( ) Rhabdomyosarcoma ( ) Adult lymphoma ( ) Insulinoma ( ) Lymphoma ( ) Nasopharyngeal carcinoma ( ) Neuroblastoma ( ) Pediatric lymphoma ( ) Small-cell lung cancer ( ) Type-1/2 diabetes ( )
UniProt ID	INSM1_HUMAN
3D Structure	Download 2D Sequence (FASTA) Download 3D Structure (PDB) Download
PDB ID	2LV2; 3ZMS
Pfam ID	PF00096
Sequence	MPRGFLVKRSKKSTPVSYRVRGGEDGDRALLLSPSCGGARAEPPAPSPVPGPLPPPPPAE RAHAALAAALACAPGPQPPPQGPRAAHFGNPEAAHPAPLYSPTRPVSREHEKHKYFERSF NLGSPVSAESFPTPAALLGGGGGGGASGAGGGGTCGGDPLLFAPAELKMGTAFSAGAEAA RGPGPGPPLPPAAALRPPGKRPPPPTAAEPPAKAVKAPGAKKPKAIRKLHFEDEVTTSPV LGLKIKEGPVEAPRGRAGGAARPLGEFICQLCKEEYADPFALAQHKCSRIVRVEYRCPEC AKVFSCPANLASHRRWHKPRPAPAAARAPEPEAAARAEAREAPGGGSDRDTPSPGGVSES GSEDGLYECHHCAKKFRRQAYLRKHLLAHHQALQAKGAPLAPPAEDLLALYPGPDEKAPQ EAAGDGEGAGVLGLSASAECHLCPVCGESFASKGAQERHLRLLHAAQVFPCKYCPATFYS SPGLTRHINKCHPSENRQVILLQVPVRPAC
Function	Sequence-specific DNA-binding transcriptional regulator that plays a key role in neurogenesis and neuroendocrine cell differentiation during embryonic and/or fetal development. Binds to the consensus sequence 5'-[TG][TC][TC][TT][GA]GGG[CG]A-3' in target promoters. Acts as a transcriptional repressor of NEUROD1 and INS expression via its interaction with cyclin CCND1 in a cell cycle-independent manner. Negatively regulates skeletal muscle-specific gene expression in endocrine cells of the pituitary by inhibiting the Notch signaling pathway. Represses target gene transcription by recruiting chromatin-modifying factors, such as HDAC1, HDAC2, HDAC3, KDM1A and RCOR1 histone deacetylases. Binds to its own promoter, suggesting autoregulation as a self-control feedback mechanism. Competes with histone H3 for the same binding site on the histone demethylase complex formed by KDM1A and RCOR1, and thereby inhibits demethylation of histone H3 at 'Lys-4'. Promotes the generation and expansion of neuronal basal progenitor cells in the developing neocortex. Involved in the differentiation of endocrine cells of the developing anterior pituitary gland, of the pancreas and intestine, and of sympatho-adrenal cells in the peripheral nervous system. Promotes cell cycle signaling arrest and inhibition of cellular proliferation.
Tissue Specificity	Expressed in pancreatic duct cells. Expressed in several tumor cell lines of neuroendocrine origin including pheochromocytoma, medullary thyroid carcinoma, insulinoma, medulloblastoma, retinoblastoma, pheochromacytoma, medullary thyroid carcinoma and small cell lung carcinoma.
Reactome Pathway	Regulation of gene expression in endocrine-committed (NEUROG3+) progenitor cells (R-HSA-210746 )

Molecular Interaction Atlas (MIA) of This DOT

37 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance
Pancreatic ductal carcinoma	DIS26F9Q	Definitive	Altered Expression	[1]
Acinar cell carcinoma	DIS37Y0J	Strong	Biomarker	[2]
Chondrosarcoma	DIS4I7JB	Strong	Biomarker	[3]
Chordoma	DISCHJE7	Strong	Biomarker	[3]
Embryonal neoplasm	DIS5MQSB	Strong	Altered Expression	[4]
Ewing sarcoma	DISQYLV3	Strong	Biomarker	[3]
Herpes simplex infection	DISL1SAV	Strong	Biomarker	[5]
Lung cancer	DISCM4YA	Strong	Biomarker	[6]
Lung carcinoma	DISTR26C	Strong	Biomarker	[6]
Medullary thyroid gland carcinoma	DISHBL3K	Strong	Biomarker	[7]
Medulloblastoma	DISZD2ZL	Strong	Biomarker	[5]
Pancreatic neuroendocrine tumor	DISDMPU0	Strong	Biomarker	[8]
Paraganglioma	DIS2XXH5	Strong	Biomarker	[9]
Pineoblastoma	DISQK8F3	Strong	Biomarker	[10]
Prostate carcinoma	DISMJPLE	Strong	Altered Expression	[2]
Squamous cell carcinoma	DISQVIFL	Strong	Biomarker	[11]
Adult glioblastoma	DISVP4LU	moderate	Biomarker	[5]
Advanced cancer	DISAT1Z9	moderate	Biomarker	[12]
Breast carcinoma	DIS2UE88	moderate	Altered Expression	[13]
Carcinoma	DISH9F1N	moderate	Biomarker	[14]
Ganglioneuroblastoma	DIS6FPB6	moderate	Altered Expression	[4]
Glioblastoma multiforme	DISK8246	moderate	Biomarker	[5]
Metastatic malignant neoplasm	DIS86UK6	moderate	Biomarker	[15]
Neuroblastic tumor	DISKWPS1	moderate	Altered Expression	[4]
Neuroendocrine cancer	DISVGJET	moderate	Biomarker	[9]
Primitive neuroectodermal tumor	DISFHXHA	moderate	Biomarker	[5]
Prostate adenocarcinoma	DISBZYU8	moderate	Altered Expression	[13]
Retinoblastoma	DISVPNPB	moderate	Biomarker	[5]
Rhabdomyosarcoma	DISNR7MS	moderate	Altered Expression	[4]
Adult lymphoma	DISK8IZR	Limited	Biomarker	[16]
Insulinoma	DISIU1JS	Limited	Altered Expression	[17]
Lymphoma	DISN6V4S	Limited	Biomarker	[16]
Nasopharyngeal carcinoma	DISAOTQ0	Limited	Biomarker	[18]
Neuroblastoma	DISVZBI4	Limited	Altered Expression	[19]
Pediatric lymphoma	DIS51BK2	Limited	Biomarker	[16]
Small-cell lung cancer	DISK3LZD	Limited	Biomarker	[20]
Type-1/2 diabetes	DISIUHAP	Limited	Altered Expression	[21]
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Molecular Interaction Atlas (MIA)

MIA Detail

Jump to Detail Molecular Interaction Atlas of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Insulinoma-associated protein 1 (INSM1).	[22]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Insulinoma-associated protein 1 (INSM1).	[23]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Insulinoma-associated protein 1 (INSM1).	[24]
Ibuprofen	DM8VCBE	Approved	Ibuprofen decreases the expression of Insulinoma-associated protein 1 (INSM1).	[25]
Rofecoxib	DM3P5DA	Approved	Rofecoxib decreases the expression of Insulinoma-associated protein 1 (INSM1).	[25]
Resveratrol	DM3RWXL	Phase 3	Resveratrol decreases the expression of Insulinoma-associated protein 1 (INSM1).	[26]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Insulinoma-associated protein 1 (INSM1).	[28]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Insulinoma-associated protein 1 (INSM1).	[29]
Paraquat	DMR8O3X	Investigative	Paraquat increases the expression of Insulinoma-associated protein 1 (INSM1).	[30]
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⏷ Show the Full List of 9 Drug(s)

1 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 Insulinoma-associated protein 1 (INSM1).	[27]
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References

1	Insulinoma-associated protein 1 expression in pancreatic neuroendocrine tumours in endoscopic ultrasound-guided fine-needle aspiration cytology: An analysis of 14 patients.Cytopathology. 2019 Mar;30(2):194-200. doi: 10.1111/cyt.12640. Epub 2018 Dec 17.
2	Insulinoma-associated protein 1 is a novel sensitive and specific marker for small cell carcinoma of the prostate.Hum Pathol. 2018 Sep;79:151-159. doi: 10.1016/j.humpath.2018.05.014. Epub 2018 Jun 6.
3	INSM1 expression and its diagnostic significance in extraskeletal myxoid chondrosarcoma.Mod Pathol. 2018 May;31(5):744-752. doi: 10.1038/modpathol.2017.189. Epub 2018 Jan 12.
4	INSM1 Expression in Peripheral Neuroblastic Tumors and Other Embryonal Neoplasms.Pediatr Dev Pathol. 2019 Oct;22(5):440-448. doi: 10.1177/1093526619843725. Epub 2019 Apr 11.
5	INSM1 promoter-driven adenoviral herpes simplex virus thymidine kinase cancer gene therapy for the treatment of primitive neuroectodermal tumors.Hum Gene Ther. 2009 Nov;20(11):1308-18. doi: 10.1089/hum.2008.168.
6	Sonic hedgehog signaling pathway promotes INSM1 transcription factor in neuroendocrine lung cancer.Cell Signal. 2018 Jun;46:83-91. doi: 10.1016/j.cellsig.2018.02.014. Epub 2018 Mar 1.
7	INSM1 is a Sensitive and Specific Marker of Neuroendocrine Differentiation in Head and Neck Tumors.Am J Surg Pathol. 2018 May;42(5):665-671. doi: 10.1097/PAS.0000000000001037.
8	Insulinoma-associated protein 1 (INSM1) is a useful marker for pancreatic neuroendocrine tumor.Med Mol Morphol. 2018 Mar;51(1):32-40. doi: 10.1007/s00795-017-0167-6. Epub 2017 Aug 28.
9	Insulinoma-associated Protein 1 (INSM1) in Thoracic Tumors is Less Sensitive but More Specific Compared With Synaptophysin, Chromogranin A, and CD56.Appl Immunohistochem Mol Morphol. 2020 Mar;28(3):237-242. doi: 10.1097/PAI.0000000000000715.
10	Molecular characterization of central neurocytomas: potential markers for tumor typing and progression.Neuropathology. 2013 Apr;33(2):149-61. doi: 10.1111/j.1440-1789.2012.01338.x. Epub 2012 Jul 23.
11	American Registry of Pathology Expert Opinions: Evaluation of poorly differentiated malignant neoplasms on limited samples - Gastrointestinal mucosal biopsies.Ann Diagn Pathol. 2020 Feb;44:151419. doi: 10.1016/j.anndiagpath.2019.151419. Epub 2019 Nov 15.
12	Insulinoma-associated protein 1 is a sensitive and specific marker of neuroendocrine lung neoplasms in cytology specimens.Cancer Cytopathol. 2018 Apr;126(4):243-252. doi: 10.1002/cncy.21972. Epub 2018 Jan 23.
13	Expression of Insulinoma-Associated Protein 1 (INSM1) and Orthopedia Homeobox (OTP) in Tumors with Neuroendocrine Differentiation at Rare Sites.Endocr Pathol. 2019 Mar;30(1):35-42. doi: 10.1007/s12022-018-9559-y.
14	INSM1 Demonstrates Superior Performance to the Individual and Combined Use of Synaptophysin, Chromogranin and CD56 for Diagnosing Neuroendocrine Tumors of the Thoracic Cavity.Am J Surg Pathol. 2017 Nov;41(11):1561-1569. doi: 10.1097/PAS.0000000000000916.
15	Insulinoma-associated protein 1 (INSM1) is a sensitive and highly specific marker of neuroendocrine differentiation in primary lung neoplasms: an immunohistochemical study of 345 cases, including 292 whole-tissue sections.Mod Pathol. 2019 Jan;32(1):100-109. doi: 10.1038/s41379-018-0122-7. Epub 2018 Aug 28.
16	A variant Burkitt-type translocation (2p-;8q+) in a patient with diffuse large cell lymphoma.Cancer Genet Cytogenet. 1987 Feb;24(2):225-9. doi: 10.1016/0165-4608(87)90103-8.
17	Alleles of Insm1 determine whether RIP1-Tag2 mice produce insulinomas or nonfunctioning pancreatic neuroendocrine tumors.Oncogenesis. 2019 Feb 22;8(3):16. doi: 10.1038/s41389-019-0127-1.
18	Insulinoma-associated protein 1 controls nasopharyngeal carcinoma to radiotherapy by modulating cyclin D1-dependent DNA repair machinery.Carcinogenesis. 2020 May 14;41(3):326-333. doi: 10.1093/carcin/bgz101.
19	5'-Iodotubercidin represses insulinoma-associated-1 expression, decreases cAMP levels, and suppresses human neuroblastoma cell growth.J Biol Chem. 2019 Apr 5;294(14):5456-5465. doi: 10.1074/jbc.RA118.006761. Epub 2019 Feb 12.
20	Triple marker composed of p16, CD56, and TTF1 shows higher sensitivity than INSM1 for diagnosis of pulmonary small cell carcinoma: proposal for a rational immunohistochemical algorithm for diagnosis of small cell carcinoma in small biopsy and cytology specimens.Hum Pathol. 2019 Mar;85:58-64. doi: 10.1016/j.humpath.2018.10.016. Epub 2018 Oct 30.
21	Haploinsufficiency of Insm1 Impairs Postnatal Baseline -Cell Mass.Diabetes. 2018 Dec;67(12):2615-2625. doi: 10.2337/db17-1330. Epub 2018 Sep 26.
22	Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
23	Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
24	Arsenic suppresses gene expression in promyelocytic leukemia cells partly through Sp1 oxidation. Blood. 2005 Jul 1;106(1):304-10.
25	Rofecoxib modulates multiple gene expression pathways in a clinical model of acute inflammatory pain. Pain. 2007 Mar;128(1-2):136-47.
26	Differential expression of genes induced by resveratrol in LNCaP cells: P53-mediated molecular targets. Int J Cancer. 2003 Mar 20;104(2):204-12.
27	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.
28	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.
29	Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
30	An in vitro strategy using multiple human induced pluripotent stem cell-derived models to assess the toxicity of chemicals: A case study on paraquat. Toxicol In Vitro. 2022 Jun;81:105333. doi: 10.1016/j.tiv.2022.105333. Epub 2022 Feb 16.