Details of Drug Off-Target (DOT)

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

• DOT Name: Leucine-rich repeat serine/threonine-protein kinase 1 (LRRK1)
• Synonyms: EC 2.7.11.1
• Gene Name: LRRK1
• Related Disease:
  Bone disease
  Late-onset Parkinson disease
  Osteoporosis
  Parkinson disease
  Parkinsonian disorder
• UniProt ID: LRRK1_HUMAN
• PDB ID: 8E04; 8E05; 8E06; 8FAC
• EC Number: 2.7.11.1
• Pfam ID: PF16095 ; PF00560 ; PF00069 ; PF08477
• Sequence:
  MAGMSQRPPSMYWCVGPEESAVCPERAMETLNGAGDTGGKPSTRGGDPAARSRRTEGIRA
  AYRRGDRGGARDLLEEACDQCASQLEKGQLLSIPAAYGDLEMVRYLLSKRLVELPTEPTD
  DNPAVVAAYFGHTAVVQELLESLPGPCSPQRLLNWMLALACQRGHLGVVKLLVLTHGADP
  ESYAVRKNEFPVIVRLPLYAAIKSGNEDIAIFLLRHGAYFCSYILLDSPDPSKHLLRKYF
  IEASPLPSSYPGKTALRVKWSHLRLPWVDLDWLIDISCQITELDLSANCLATLPSVIPWG
  LINLRKLNLSDNHLGELPGVQSSDEIICSRLLEIDISSNKLSHLPPGFLHLSKLQKLTAS
  KNCLEKLFEEENATNWIGLRKLQELDISDNKLTELPALFLHSFKSLNSLNVSRNNLKVFP
  DPWACPLKCCKASRNALECLPDKMAVFWKNHLKDVDFSENALKEVPLGLFQLDALMFLRL
  QGNQLAALPPQEKWTCRQLKTLDLSRNQLGKNEDGLKTKRIAFFTTRGRQRSGTEAASVL
  EFPAFLSESLEVLCLNDNHLDTVPPSVCLLKSLSELYLGNNPGLRELPPELGQLGNLWQL
  DTEDLTISNVPAEIQKEGPKAMLSYLRAQLRKAEKCKLMKMIIVGPPRQGKSTLLEILQT
  GRAPQVVHGEATIRTTKWELQRPAGSRAKVESVEFNVWDIGGPASMATVNQCFFTDKALY
  VVVWNLALGEEAVANLQFWLLNIEAKAPNAVVLVVGTHLDLIEAKFRVERIATLRAYVLA
  LCRSPSGSRATGFPDITFKHLHEISCKSLEGQEGLRQLIFHVTCSMKDVGSTIGCQRLAG
  RLIPRSYLSLQEAVLAEQQRRSRDDDVQYLTDRQLEQLVEQTPDNDIKDYEDLQSAISFL
  IETGTLLHFPDTSHGLRNLYFLDPIWLSECLQRIFNIKGSRSVAKNGVIRAEDLRMLLVG
  TGFTQQTEEQYFQFLAKFEIALPVANDSYLLPHLLPSKPGLDTHGMRHPTANTIQRVFKM
  SFVPVGFWQRFIARMLISLAEMDLQLFENKKNTKSRNRKVTIYSFTGNQRNRCSTFRVKR
  NQTIYWQEGLLVTFDGGYLSVESSDVNWKKKKSGGMKIVCQSEVRDFSAMAFITDHVNSL
  IDQWFPALTATESDGTPLMEQYVPCPVCETAWAQHTDPSEKSEDVQYFDMEDCVLTAIER
  DFISCPRHPDLPVPLQELVPELFMTDFPARLFLENSKLEHSEDEGSVLGQGGSGTVIYRA
  RYQGQPVAVKRFHIKKFKNFANVPADTMLRHLRATDAMKNFSEFRQEASMLHALQHPCIV
  ALIGISIHPLCFALELAPLSSLNTVLSENARDSSFIPLGHMLTQKIAYQIASGLAYLHKK
  NIIFCDLKSDNILVWSLDVKEHINIKLSDYGISRQSFHEGALGVEGTPGYQAPEIRPRIV
  YDEKVDMFSYGMVLYELLSGQRPALGHHQLQIAKKLSKGIRPVLGQPEEVQFRRLQALMM
  ECWDTKPEKRPLALSVVSQMKDPTFATFMYELCCGKQTAFFSSQGQEYTVVFWDGKEESR
  NYTVVNTEKGLMEVQRMCCPGMKVSCQLQVQRSLWTATEDQKIYIYTLKGMCPLNTPQQA
  LDTPAVVTCFLAVPVIKKNSYLVLAGLADGLVAVFPVVRGTPKDSCSYLCSHTANRSKFS
  IADEDARQNPYPVKAMEVVNSGSEVWYSNGPGLLVIDCASLEICRRLEPYMAPSMVTSVV
  CSSEGRGEEVVWCLDDKANSLVMYHSTTYQLCARYFCGVPSPLRDMFPVRPLDTEPPAAS
  HTANPKVPEGDSIADVSIMYSEELGTQILIHQESLTDYCSMSSYSSSPPRQAARSPSSLP
  SSPASSSSVPFSTDCEDSDMLHTPGAASDRSEHDLTPMDGETFSQHLQAVKILAVRDLIW
  VPRRGGDVIVIGLEKDSGAQRGRVIAVLKARELTPHGVLVDAAVVAKDTVVCTFENENTE
  WCLAVWRGWGAREFDIFYQSYEELGRLEACTRKRR
• Function: Plays a role in the negative regulation of bone mass, acting through the maturation of osteoclasts.

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Bone disease	DISE1F82	Strong	Biomarker	[1]
Late-onset Parkinson disease	DIS9IOUI	Strong	Genetic Variation	[2]
Osteoporosis	DISF2JE0	Strong	Biomarker	[1]
Parkinson disease	DISQVHKL	Strong	Genetic Variation	[3]
Parkinsonian disorder	DISHGY45	Strong	Genetic Variation	[4]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of Leucine-rich repeat serine/threonine-protein kinase 1 (LRRK1).	[5]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Leucine-rich repeat serine/threonine-protein kinase 1 (LRRK1).	[6]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Leucine-rich repeat serine/threonine-protein kinase 1 (LRRK1).	[8]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Leucine-rich repeat serine/threonine-protein kinase 1 (LRRK1).	[9]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Leucine-rich repeat serine/threonine-protein kinase 1 (LRRK1).	[9]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Leucine-rich repeat serine/threonine-protein kinase 1 (LRRK1).	[10]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Leucine-rich repeat serine/threonine-protein kinase 1 (LRRK1).	[11]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Leucine-rich repeat serine/threonine-protein kinase 1 (LRRK1).	[13]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Leucine-rich repeat serine/threonine-protein kinase 1 (LRRK1).	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Leucine-rich repeat serine/threonine-protein kinase 1 (LRRK1).	[7]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Leucine-rich repeat serine/threonine-protein kinase 1 (LRRK1).	[12]

References

• [1] Role and mechanism of action of leucine-rich repeat kinase 1 in bone.Bone Res. 2017 Mar 14;5:17003. doi: 10.1038/boneres.2017.3. eCollection 2017.
• [2] Variants in the LRRK1 gene and susceptibility to Parkinson's disease in Norway.Neurosci Lett. 2007 Apr 18;416(3):299-301. doi: 10.1016/j.neulet.2007.02.020. Epub 2007 Feb 12.
• [3] Genetic Analysis of LRRK1 and LRRK2 Variants in Essential Tremor Patients.Genet Test Mol Biomarkers. 2018 Jun;22(6):398-402. doi: 10.1089/gtmb.2017.0277. Epub 2018 May 29.
• [4] Heterodimerization of Lrrk1-Lrrk2: Implications for LRRK2-associated Parkinson disease.Mech Ageing Dev. 2010 Mar;131(3):210-4. doi: 10.1016/j.mad.2010.01.009. Epub 2010 Feb 6.
• [5] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [6] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [7] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [8] Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
• [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] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [11] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [12] 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.
• [13] 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.
• [14] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.