Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT3SG7ZR)

• DOT Name: Prelamin-A/C (LMNA)
• Gene Name: LMNA
• Related Disease:
  Congestive heart failure
  Dilated cardiomyopathy
  Dilated cardiomyopathy 1A
  Emery-Dreifuss muscular dystrophy 2, autosomal dominant
  Familial partial lipodystrophy, Dunnigan type
  Hutchinson-Gilford progeria syndrome
  Lung adenocarcinoma
  Achalasia
  Arrhythmia
  Atherosclerosis
  Atrioventricular block
  Atrioventricular dissociation
  Central core myopathy
  Charcot-Marie-Tooth disease type 2B1
  Charcot-Marie-Tooth disease type 3
  Congenital fiber-type disproportion myopathy
  Congenital muscular dystrophy
  Emery-Dreifuss muscular dystrophy 3, autosomal recessive
  Heart-hand syndrome, Slovenian type
  Hereditary motor and sensory neuropathy
  High blood pressure
  Hyperinsulinemia
  Left ventricular noncompaction
  Limb-girdle muscular dystrophy
  Mandibuloacral dysplasia with type A lipodystrophy
  Muscular dystrophy
  Myopathy
  Neuromuscular disease
  Otitis media
  PPARG-related familial partial lipodystrophy
  Scleroderma
  Ventricular tachycardia
  X-linked Emery-Dreifuss muscular dystrophy
  Monogenic diabetes
  Atypical Werner syndrome
  Autosomal dominant Emery-Dreifuss muscular dystrophy
  Autosomal semi-dominant severe lipodystrophic laminopathy
  Congenital muscular dystrophy due to LMNA mutation
  Dilated cardiomyopathy-hypergonadotropic hypogonadism syndrome
  LMNA-related cardiocutaneous progeria syndrome
  Obsolete autosomal recessive Emery-Dreifuss muscular dystrophy
  Obsolete familial isolated dilated cardiomyopathy
  Obsolete lethal restrictive dermopathy
  Arrhythmogenic right ventricular cardiomyopathy
  Arteriosclerosis
  Congenital generalized lipodystrophy
  Congenital myopathy
  Focal segmental glomerulosclerosis
  Mandibuloacral dysplasia
  Multiminicore myopathy
  Nemaline myopathy
  Restrictive dermopathy
  Restrictive dermopathy 1
• UniProt ID: LMNA_HUMAN
• PDB ID: 1IFR; 1IVT; 1X8Y; 2XV5; 2YPT; 3GEF; 3V4Q; 3V4W; 3V5B; 6GHD; 6JLB; 6RPR; 6SNZ; 6YF5; 6YJD; 7CRG; 7D9N; 7WZZ; 7X1B; 7X5D; 7YVD; 7Z21
• Pfam ID: PF00038 ; PF00932
• Sequence:
  METPSQRRATRSGAQASSTPLSPTRITRLQEKEDLQELNDRLAVYIDRVRSLETENAGLR
  LRITESEEVVSREVSGIKAAYEAELGDARKTLDSVAKERARLQLELSKVREEFKELKARN
  TKKEGDLIAAQARLKDLEALLNSKEAALSTALSEKRTLEGELHDLRGQVAKLEAALGEAK
  KQLQDEMLRRVDAENRLQTMKEELDFQKNIYSEELRETKRRHETRLVEIDNGKQREFESR
  LADALQELRAQHEDQVEQYKKELEKTYSAKLDNARQSAERNSNLVGAAHEELQQSRIRID
  SLSAQLSQLQKQLAAKEAKLRDLEDSLARERDTSRRLLAEKEREMAEMRARMQQQLDEYQ
  ELLDIKLALDMEIHAYRKLLEGEEERLRLSPSPTSQRSRGRASSHSSQTQGGGSVTKKRK
  LESTESRSSFSQHARTSGRVAVEEVDEEGKFVRLRNKSNEDQSMGNWQIKRQNGDDPLLT
  YRFPPKFTLKAGQVVTIWAAGAGATHSPPTDLVWKAQNTWGCGNSLRTALINSTGEEVAM
  RKLVRSVTVVEDDEDEDGDDLLHHHHGSHCSSSGDPAEYNLRSRTVLCGTCGQPADKASA
  SGSGAQVGGPISSGSSASSVTVTRSYRSVGGSGGGSFGDNLVTRSYLLGNSSPRTQSPQN
  CSIM
• Function: [Lamin-A/C]: Lamins are intermediate filament proteins that assemble into a filamentous meshwork, and which constitute the major components of the nuclear lamina, a fibrous layer on the nucleoplasmic side of the inner nuclear membrane. Lamins provide a framework for the nuclear envelope, bridging the nuclear envelope and chromatin, thereby playing an important role in nuclear assembly, chromatin organization, nuclear membrane and telomere dynamics. Lamin A and C also regulate matrix stiffness by conferring nuclear mechanical properties. The structural integrity of the lamina is strictly controlled by the cell cycle, as seen by the disintegration and formation of the nuclear envelope in prophase and telophase, respectively. Lamin A and C are present in equal amounts in the lamina of mammals. Also invoved in DNA repair: recruited by DNA repair proteins XRCC4 and IFFO1 to the DNA double-strand breaks (DSBs) to prevent chromosome translocation by immobilizing broken DNA ends. Required for normal development of peripheral nervous system and skeletal muscle and for muscle satellite cell proliferation. Required for osteoblastogenesis and bone formation. Also prevents fat infiltration of muscle and bone marrow, helping to maintain the volume and strength of skeletal muscle and bone. Required for cardiac homeostasis ; [Prelamin-A/C]: Prelamin-A/C can accelerate smooth muscle cell senescence. It acts to disrupt mitosis and induce DNA damage in vascular smooth muscle cells (VSMCs), leading to mitotic failure, genomic instability, and premature senescence.
• Tissue Specificity: In the arteries, prelamin-A/C accumulation is not observed in young healthy vessels but is prevalent in medial vascular smooth muscle cells (VSMCs) from aged individuals and in atherosclerotic lesions, where it often colocalizes with senescent and degenerate VSMCs. Prelamin-A/C expression increases with age and disease. In normal aging, the accumulation of prelamin-A/C is caused in part by the down-regulation of ZMPSTE24/FACE1 in response to oxidative stress.
• KEGG Pathway:
  Apoptosis (hsa04210)
  Cytoskeleton in muscle cells (hsa04820)
  Hypertrophic cardiomyopathy (hsa05410)
  Arrhythmogenic right ventricular cardiomyopathy (hsa05412)
  Dilated cardiomyopathy (hsa05414)
• Reactome Pathway:
  (Name not found)
  Initiation of Nuclear Envelope (NE) Reformation (R-HSA-2995383)
  XBP1(S) activates chaperone genes (R-HSA-381038)
  Depolymerization of the Nuclear Lamina (R-HSA-4419969)
  Signaling by BRAF and RAF1 fusions (R-HSA-6802952)
  Nuclear Envelope Breakdown (R-HSA-2980766)

Molecular Interaction Atlas (MIA) of This DOT

53 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Congestive heart failure	DIS32MEA	Definitive	Genetic Variation	[1]
Dilated cardiomyopathy	DISX608J	Definitive	Autosomal dominant	[2]
Dilated cardiomyopathy 1A	DIS0RK9Z	Definitive	Autosomal dominant	[3]
Emery-Dreifuss muscular dystrophy 2, autosomal dominant	DIS4FT32	Definitive	Autosomal dominant	[4]
Familial partial lipodystrophy, Dunnigan type	DISD1N0B	Definitive	Autosomal dominant	[5]
Hutchinson-Gilford progeria syndrome	DISY55BU	Definitive	Autosomal dominant	[4]
Lung adenocarcinoma	DISD51WR	Definitive	Altered Expression	[6]
Achalasia	DISK845N	Strong	Biomarker	[7]
Arrhythmia	DISFF2NI	Strong	Genetic Variation	[8]
Atherosclerosis	DISMN9J3	Strong	Genetic Variation	[9]
Atrioventricular block	DIS8YLE6	Strong	Autosomal dominant	[10]
Atrioventricular dissociation	DIS3N5H4	Strong	Biomarker	[11]
Central core myopathy	DIS18AZZ	Strong	Genetic Variation	[12]
Charcot-Marie-Tooth disease type 2B1	DISRZRGX	Strong	Autosomal recessive	[13]
Charcot-Marie-Tooth disease type 3	DIS6DQK1	Strong	Biomarker	[13]
Congenital fiber-type disproportion myopathy	DISU9T2M	Strong	Genetic Variation	[14]
Congenital muscular dystrophy	DISKY7OY	Strong	Biomarker	[15]
Emery-Dreifuss muscular dystrophy 3, autosomal recessive	DIST0JEG	Strong	Autosomal recessive	[16]
Heart-hand syndrome, Slovenian type	DIS54QNM	Strong	Autosomal dominant	[11]
Hereditary motor and sensory neuropathy	DISR0X2K	Strong	Biomarker	[13]
High blood pressure	DISY2OHH	Strong	Altered Expression	[17]
Hyperinsulinemia	DISIDWT6	Strong	Genetic Variation	[18]
Left ventricular noncompaction	DISJ4QEG	Strong	Genetic Variation	[19]
Limb-girdle muscular dystrophy	DISI9Y1Z	Strong	Biomarker	[20]
Mandibuloacral dysplasia with type A lipodystrophy	DISZZ6TI	Strong	Autosomal recessive	[21]
Muscular dystrophy	DISJD6P7	Strong	Genetic Variation	[22]
Myopathy	DISOWG27	Strong	Genetic Variation	[23]
Neuromuscular disease	DISQTIJZ	Strong	Genetic Variation	[24]
Otitis media	DISGZDUO	Strong	Biomarker	[25]
PPARG-related familial partial lipodystrophy	DISVYGXS	Strong	Biomarker	[26]
Scleroderma	DISVQ342	Strong	Genetic Variation	[27]
Ventricular tachycardia	DISIBXJ3	Strong	Genetic Variation	[28]
X-linked Emery-Dreifuss muscular dystrophy	DISDPMZ3	Strong	Biomarker	[29]
Monogenic diabetes	DISEB8Q0	moderate	CausalMutation	[30]
Atypical Werner syndrome	DIS9SLU2	Supportive	Autosomal dominant	[31]
Autosomal dominant Emery-Dreifuss muscular dystrophy	DISL8GMY	Supportive	Autosomal dominant	[32]
Autosomal semi-dominant severe lipodystrophic laminopathy	DIS0BB6S	Supportive	Semidominant	[33]
Congenital muscular dystrophy due to LMNA mutation	DISEHF4P	Supportive	Autosomal dominant	[34]
Dilated cardiomyopathy-hypergonadotropic hypogonadism syndrome	DISW3YUD	Supportive	Autosomal recessive	[35]
LMNA-related cardiocutaneous progeria syndrome	DIST7348	Supportive	Autosomal dominant	[36]
Obsolete autosomal recessive Emery-Dreifuss muscular dystrophy	DISGD4FN	Supportive	Autosomal recessive	[32]
Obsolete familial isolated dilated cardiomyopathy	DIS4FXO4	Supportive	Autosomal dominant	[37]
Obsolete lethal restrictive dermopathy	DISI414T	Supportive	Autosomal dominant	[38]
Arrhythmogenic right ventricular cardiomyopathy	DIS3V2BE	Limited	Autosomal dominant	[2]
Arteriosclerosis	DISK5QGC	Limited	Genetic Variation	[9]
Congenital generalized lipodystrophy	DIS4XF8N	Limited	Genetic Variation	[39]
Congenital myopathy	DISLSK9G	Limited	Biomarker	[40]
Focal segmental glomerulosclerosis	DISJNHH0	Limited	Biomarker	[41]
Mandibuloacral dysplasia	DISMOYL1	Limited	Genetic Variation	[42]
Multiminicore myopathy	DISE6VYN	Limited	Biomarker	[40]
Nemaline myopathy	DIS5IYLY	Limited	Biomarker	[40]
Restrictive dermopathy	DIS2IBA1	Limited	Biomarker	[43]
Restrictive dermopathy 1	DISBCVN8	Limited	Autosomal dominant	[4]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Mitomycin	DMH0ZJE	Approved	Prelamin-A/C (LMNA) affects the response to substance of Mitomycin.	[84]

29 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 Prelamin-A/C (LMNA).	[44]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Prelamin-A/C (LMNA).	[45]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Prelamin-A/C (LMNA).	[47]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Prelamin-A/C (LMNA).	[49]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Prelamin-A/C (LMNA).	[51]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Prelamin-A/C (LMNA).	[52]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Prelamin-A/C (LMNA).	[53]
Marinol	DM70IK5	Approved	Marinol decreases the expression of Prelamin-A/C (LMNA).	[54]
Zoledronate	DMIXC7G	Approved	Zoledronate decreases the expression of Prelamin-A/C (LMNA).	[55]
Selenium	DM25CGV	Approved	Selenium increases the expression of Prelamin-A/C (LMNA).	[56]
Demecolcine	DMCZQGK	Approved	Demecolcine increases the expression of Prelamin-A/C (LMNA).	[58]
Hydroquinone	DM6AVR4	Approved	Hydroquinone affects the expression of Prelamin-A/C (LMNA).	[60]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone affects the expression of Prelamin-A/C (LMNA).	[61]
Menthol	DMG2KW7	Approved	Menthol increases the expression of Prelamin-A/C (LMNA).	[62]
Ritonavir	DMU764S	Approved	Ritonavir increases the expression of Prelamin-A/C (LMNA).	[63]
Dopamine	DMPGUCF	Approved	Dopamine increases the expression of Prelamin-A/C (LMNA).	[64]
Aminoglutethimide	DMWFHMZ	Approved	Aminoglutethimide decreases the expression of Prelamin-A/C (LMNA).	[66]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of Prelamin-A/C (LMNA).	[70]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Prelamin-A/C (LMNA).	[56]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Prelamin-A/C (LMNA).	[72]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Prelamin-A/C (LMNA).	[73]
Tetrandrine	DMAOJBX	Phase 1	Tetrandrine increases the expression of Prelamin-A/C (LMNA).	[75]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Prelamin-A/C (LMNA).	[76]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Prelamin-A/C (LMNA).	[79]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of Prelamin-A/C (LMNA).	[80]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Prelamin-A/C (LMNA).	[58]
[3H]methyltrienolone	DMTSGOW	Investigative	[3H]methyltrienolone decreases the expression of Prelamin-A/C (LMNA).	[81]
Butanoic acid	DMTAJP7	Investigative	Butanoic acid decreases the expression of Prelamin-A/C (LMNA).	[82]
	DMQNVR8		increases the expression of Prelamin-A/C (LMNA).	[63]

8 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the cleavage of Prelamin-A/C (LMNA).	[46]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil increases the cleavage of Prelamin-A/C (LMNA).	[57]
Bortezomib	DMNO38U	Approved	Bortezomib increases the cleavage of Prelamin-A/C (LMNA).	[59]
Deoxycholic acid	DM3GYAL	Approved	Deoxycholic acid increases the cleavage of Prelamin-A/C (LMNA).	[65]
Resveratrol	DM3RWXL	Phase 3	Resveratrol increases the cleavage of Prelamin-A/C (LMNA).	[69]
PMID25656651-Compound-5	DMAI95U	Patented	PMID25656651-Compound-5 increases the cleavage of Prelamin-A/C (LMNA).	[78]
Staurosporine	DM0E9BR	Investigative	Staurosporine increases the cleavage of Prelamin-A/C (LMNA).	[83]
Chelerythrine	DMCP1G9	Investigative	Chelerythrine increases the cleavage of Prelamin-A/C (LMNA).	[83]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Estradiol	DMUNTE3	Approved	Estradiol increases the phosphorylation of Prelamin-A/C (LMNA).	[48]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Prelamin-A/C (LMNA).	[50]
Lopinavir	DMITQS0	Approved	Lopinavir increases the farnesylation of Prelamin-A/C (LMNA).	[67]
Lonafarnib	DMGM2Z6	Approved	Lonafarnib decreases the farnesylation of Prelamin-A/C (LMNA).	[68]
G1	DMTV42K	Phase 1/2	G1 increases the phosphorylation of Prelamin-A/C (LMNA).	[48]
TAK-243	DM4GKV2	Phase 1	TAK-243 decreases the sumoylation of Prelamin-A/C (LMNA).	[74]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Prelamin-A/C (LMNA).	[77]
Coumarin	DM0N8ZM	Investigative	Coumarin affects the phosphorylation of Prelamin-A/C (LMNA).	[77]

2 Drug(s) Affected the Biochemical Pathways of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
DNCB	DMDTVYC	Phase 2	DNCB increases the metabolism of Prelamin-A/C (LMNA).	[71]
cinnamaldehyde	DMZDUXG	Investigative	cinnamaldehyde increases the metabolism of Prelamin-A/C (LMNA).	[71]

References

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