Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTN535SU)

• DOT Name: Four and a half LIM domains protein 1 (FHL1)
• Synonyms: FHL-1; Skeletal muscle LIM-protein 1; SLIM; SLIM-1
• Gene Name: FHL1
• Related Disease:
  X-linked Emery-Dreifuss muscular dystrophy
  X-linked myopathy with postural muscle atrophy
  Myopathy, reducing body, X-linked, early-onset, severe
  Reducing body myopathy
  X-linked scapuloperoneal muscular dystrophy
• UniProt ID: FHL1_HUMAN
• PDB ID: 1X63; 2CUP; 2CUR; 2EGQ
• Pfam ID: PF00412
• Sequence:
  MAEKFDCHYCRDPLQGKKYVQKDGHHCCLKCFDKFCANTCVECRKPIGADSKEVHYKNRF
  WHDTCFRCAKCLHPLANETFVAKDNKILCNKCTTREDSPKCKGCFKAIVAGDQNVEYKGT
  VWHKDCFTCSNCKQVIGTGSFFPKGEDFYCVTCHETKFAKHCVKCNKAITSGGITYQDQP
  WHADCFVCVTCSKKLAGQRFTAVEDQYYCVDCYKNFVAKKCAGCKNPITGKRTVSRVSHP
  VSKARKPPVCHGKRLPLTLFPSANLRGRHPGGERTCPSWVVVLYRKNRSLAAPRGPGLVK
  APVWWPMKDNPGTTTASTAKNAP
• Function: May have an involvement in muscle development or hypertrophy.
• Tissue Specificity: Isoform 1 is highly expressed in skeletal muscle and to a lesser extent in heart, placenta, ovary, prostate, testis, small intestine, colon and spleen. Expression is barely detectable in brain, lung, liver, kidney, pancreas, thymus and peripheral blood leukocytes. Isoform 2 is expressed in brain, skeletal muscle and to a lesser extent in heart, colon, prostate and small intestine. Isoform 3 is expressed in testis, heart and skeletal muscle.
• KEGG Pathway:
  JAK-STAT sig.ling pathway (hsa04630)
  Cytoskeleton in muscle cells (hsa04820)

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
X-linked Emery-Dreifuss muscular dystrophy	DISDPMZ3	Definitive	Autosomal dominant	[1]
X-linked myopathy with postural muscle atrophy	DISPBT0K	Definitive	X-linked	[2]
Myopathy, reducing body, X-linked, early-onset, severe	DISX4QF9	Strong	X-linked	[3]
Reducing body myopathy	DISFDWS0	Supportive	X-linked	[4]
X-linked scapuloperoneal muscular dystrophy	DISBYRCR	Supportive	X-linked	[5]

This DOT Affected the Drug Response of 5 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Etoposide	DMNH3PG	Approved	Four and a half LIM domains protein 1 (FHL1) affects the response to substance of Etoposide.	[28]
Paclitaxel	DMLB81S	Approved	Four and a half LIM domains protein 1 (FHL1) increases the response to substance of Paclitaxel.	[29]
Mitomycin	DMH0ZJE	Approved	Four and a half LIM domains protein 1 (FHL1) affects the response to substance of Mitomycin.	[28]
Topotecan	DMP6G8T	Approved	Four and a half LIM domains protein 1 (FHL1) affects the response to substance of Topotecan.	[28]
Capecitabine	DMTS85L	Approved	Four and a half LIM domains protein 1 (FHL1) decreases the response to substance of Capecitabine.	[29]

4 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 Four and a half LIM domains protein 1 (FHL1).	[6]
Decitabine	DMQL8XJ	Approved	Decitabine affects the methylation of Four and a half LIM domains protein 1 (FHL1).	[15]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Four and a half LIM domains protein 1 (FHL1).	[22]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Four and a half LIM domains protein 1 (FHL1).	[24]

19 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 Four and a half LIM domains protein 1 (FHL1).	[7]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Four and a half LIM domains protein 1 (FHL1).	[8]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Four and a half LIM domains protein 1 (FHL1).	[9]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Four and a half LIM domains protein 1 (FHL1).	[10]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Four and a half LIM domains protein 1 (FHL1).	[11]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Four and a half LIM domains protein 1 (FHL1).	[12]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Four and a half LIM domains protein 1 (FHL1).	[13]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Four and a half LIM domains protein 1 (FHL1).	[14]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Four and a half LIM domains protein 1 (FHL1).	[16]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of Four and a half LIM domains protein 1 (FHL1).	[17]
Folic acid	DMEMBJC	Approved	Folic acid affects the expression of Four and a half LIM domains protein 1 (FHL1).	[18]
Dasatinib	DMJV2EK	Approved	Dasatinib increases the expression of Four and a half LIM domains protein 1 (FHL1).	[19]
Pioglitazone	DMKJ485	Approved	Pioglitazone increases the expression of Four and a half LIM domains protein 1 (FHL1).	[20]
Isoproterenol	DMK7MEY	Approved	Isoproterenol decreases the expression of Four and a half LIM domains protein 1 (FHL1).	[21]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Four and a half LIM domains protein 1 (FHL1).	[14]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Four and a half LIM domains protein 1 (FHL1).	[23]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of Four and a half LIM domains protein 1 (FHL1).	[25]
chloropicrin	DMSGBQA	Investigative	chloropicrin decreases the expression of Four and a half LIM domains protein 1 (FHL1).	[26]
Manganese	DMKT129	Investigative	Manganese decreases the expression of Four and a half LIM domains protein 1 (FHL1).	[27]

References

• [1] Evidence for FHL1 as a novel disease gene for isolated hypertrophic cardiomyopathy. Hum Mol Genet. 2012 Jul 15;21(14):3237-54. doi: 10.1093/hmg/dds157. Epub 2012 Apr 20.
• [2] Three novel FHL1 variants cause a mild phenotype of Emery-Dreifuss muscular dystrophy. Hum Mutat. 2022 Sep;43(9):1234-1238. doi: 10.1002/humu.24415. Epub 2022 Jul 16.
• [3] An X-linked myopathy with postural muscle atrophy and generalized hypertrophy, termed XMPMA, is caused by mutations in FHL1. Am J Hum Genet. 2008 Jan;82(1):88-99. doi: 10.1016/j.ajhg.2007.09.004.
• [4] Proteomic identification of FHL1 as the protein mutated in human reducing body myopathy. J Clin Invest. 2008 Mar;118(3):904-12. doi: 10.1172/JCI34450.
• [5] X-linked dominant scapuloperoneal myopathy is due to a mutation in the gene encoding four-and-a-half-LIM protein 1. Am J Hum Genet. 2008 Jan;82(1):208-13. doi: 10.1016/j.ajhg.2007.09.013.
• [6] 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.
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• [9] 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.
• [10] Long-term estrogen exposure promotes carcinogen bioactivation, induces persistent changes in gene expression, and enhances the tumorigenicity of MCF-7 human breast cancer cells. Toxicol Appl Pharmacol. 2009 Nov 1;240(3):355-66.
• [11] 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.
• [12] 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.
• [13] An approach to elucidate potential mechanism of renal toxicity of arsenic trioxide. Exp Hematol. 2007 Feb;35(2):252-62.
• [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] Ornithine decarboxylase antizyme upregulates DNA-dependent protein kinase and enhances the nonhomologous end-joining repair of DNA double-strand breaks in human oral cancer cells. Biochemistry. 2007 Aug 7;46(31):8920-32. doi: 10.1021/bi7000328. Epub 2007 Jul 14.
• [16] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
• [17] Gene expression profile of human lymphoid CEM cells sensitive and resistant to glucocorticoid-evoked apoptosis. Genomics. 2003 Jun;81(6):543-55.
• [18] Folate deficiency in normal human fibroblasts leads to altered expression of genes primarily linked to cell signaling, the cytoskeleton and extracellular matrix. J Nutr Biochem. 2007 Aug;18(8):541-52. doi: 10.1016/j.jnutbio.2006.11.002. Epub 2007 Feb 22.
• [19] Dasatinib reverses cancer-associated fibroblasts (CAFs) from primary lung carcinomas to a phenotype comparable to that of normal fibroblasts. Mol Cancer. 2010 Jun 27;9:168.
• [20] Peroxisome proliferator activated receptor gamma (PPAR-gama) ligand pioglitazone regulated gene networks in term human primary trophoblast cells. Reprod Toxicol. 2018 Oct;81:99-107.
• [21] Isoproterenol effects evaluated in heart slices of human and rat in comparison to rat heart in vivo. Toxicol Appl Pharmacol. 2014 Jan 15;274(2):302-12.
• [22] 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.
• [23] 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.
• [24] Expression and DNA methylation changes in human breast epithelial cells after bisphenol A exposure. Int J Oncol. 2012 Jul;41(1):369-77.
• [25] Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol. 2020 Feb;136:111047. doi: 10.1016/j.fct.2019.111047. Epub 2019 Dec 12.
• [26] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.
• [27] Gene expression profiling of human primary astrocytes exposed to manganese chloride indicates selective effects on several functions of the cells. Neurotoxicology. 2007 May;28(3):478-89.
• [28] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.
• [29] Gene expression analysis using human cancer xenografts to identify novel predictive marker genes for the efficacy of 5-fluorouracil-based drugs. Cancer Sci. 2006 Jun;97(6):510-22. doi: 10.1111/j.1349-7006.2006.00204.x.