Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTVJ03NZ)

• DOT Name: Protein bicaudal D homolog 2 (BICD2)
• Synonyms: Bic-D 2
• Gene Name: BICD2
• Related Disease:
  Arthrogryposis
  Autosomal dominant childhood-onset proximal spinal muscular atrophy with contractures
  Autosomal dominant childhood-onset proximal spinal muscular atrophy without contractures
  Bilateral perisylvian polymicrogyria
  Hereditary motor and sensory neuropathy
  Hereditary spastic paraplegia
  Hydrops fetalis
  Myopathy
  Myositis disease
  Neuromuscular disease
  Non-small-cell lung cancer
  Osteoporosis
  Proximal spinal muscular atrophy
  Systemic sclerosis
  Vascular purpura
  Pancreatic cancer
  Amyotrophic lateral sclerosis
  Classic lissencephaly
  Nervous system disease
  Spinal muscular atrophy
• UniProt ID: BICD2_HUMAN
• PDB ID: 6OFP; 6PSE
• Pfam ID: PF09730
• Sequence:
  MSAPSEEEEYARLVMEAQPEWLRAEVKRLSHELAETTREKIQAAEYGLAVLEEKHQLKLQ
  FEELEVDYEAIRSEMEQLKEAFGQAHTNHKKVAADGESREESLIQESASKEQYYVRKVLE
  LQTELKQLRNVLTNTQSENERLASVAQELKEINQNVEIQRGRLRDDIKEYKFREARLLQD
  YSELEEENISLQKQVSVLRQNQVEFEGLKHEIKRLEEETEYLNSQLEDAIRLKEISERQL
  EEALETLKTEREQKNSLRKELSHYMSINDSFYTSHLHVSLDGLKFSDDAAEPNNDAEALV
  NGFEHGGLAKLPLDNKTSTPKKEGLAPPSPSLVSDLLSELNISEIQKLKQQLMQMEREKA
  GLLATLQDTQKQLEHTRGSLSEQQEKVTRLTENLSALRRLQASKERQTALDNEKDRDSHE
  DGDYYEVDINGPEILACKYHVAVAEAGELREQLKALRSTHEAREAQHAEEKGRYEAEGQA
  LTEKVSLLEKASRQDRELLARLEKELKKVSDVAGETQGSLSVAQDELVTFSEELANLYHH
  VCMCNNETPNRVMLDYYREGQGGAGRTSPGGRTSPEARGRRSPILLPKGLLAPEAGRADG
  GTGDSSPSPGSSLPSPLSDPRREPMNIYNLIAIIRDQIKHLQAAVDRTTELSRQRIASQE
  LGPAVDKDKEALMEEILKLKSLLSTKREQITTLRTVLKANKQTAEVALANLKSKYENEKA
  MVTETMMKLRNELKALKEDAATFSSLRAMFATRCDEYITQLDEMQRQLAAAEDEKKTLNS
  LLRMAIQQKLALTQRLELLELDHEQTRRGRAKAAPKTKPATPSL
• Function: Acts as an adapter protein linking the dynein motor complex to various cargos and converts dynein from a non-processive to a highly processive motor in the presence of dynactin. Facilitates and stabilizes the interaction between dynein and dynactin and activates dynein processivity (the ability to move along a microtubule for a long distance without falling off the track). Facilitates the binding of RAB6A to the Golgi by stabilizing its GTP-bound form. Regulates coat complex coatomer protein I (COPI)-independent Golgi-endoplasmic reticulum transport via its interaction with RAB6A and recruitment of the dynein-dynactin motor complex. Contributes to nuclear and centrosomal positioning prior to mitotic entry through regulation of both dynein and kinesin-1. During G2 phase of the cell cycle, associates with RANBP2 at the nuclear pores and recruits dynein and dynactin to the nuclear envelope to ensure proper positioning of the nucleus relative to centrosomes prior to the onset of mitosis.
• Tissue Specificity: Ubiquitous.
• KEGG Pathway: Viral life cycle - HIV-1 (hsa03250)
• Reactome Pathway: COPI-independent Golgi-to-ER retrograde traffic (R-HSA-6811436)

Molecular Interaction Atlas (MIA) of This DOT

20 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Arthrogryposis	DISC81CM	Strong	Genetic Variation	[1]
Autosomal dominant childhood-onset proximal spinal muscular atrophy with contractures	DISHC3JD	Strong	Autosomal dominant	[2]
Autosomal dominant childhood-onset proximal spinal muscular atrophy without contractures	DISHY37K	Strong	Genetic Variation	[3]
Bilateral perisylvian polymicrogyria	DISIF9XK	Strong	Genetic Variation	[4]
Hereditary motor and sensory neuropathy	DISR0X2K	Strong	Genetic Variation	[5]
Hereditary spastic paraplegia	DISGZQV1	Strong	Genetic Variation	[5]
Hydrops fetalis	DISD9BBF	Strong	Biomarker	[6]
Myopathy	DISOWG27	Strong	Genetic Variation	[7]
Myositis disease	DISCIXF0	Strong	Biomarker	[8]
Neuromuscular disease	DISQTIJZ	Strong	Biomarker	[9]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[10]
Osteoporosis	DISF2JE0	Strong	Biomarker	[11]
Proximal spinal muscular atrophy	DIS0R70E	Strong	Genetic Variation	[12]
Systemic sclerosis	DISF44L6	Strong	Biomarker	[8]
Vascular purpura	DIS6ZZMF	Strong	Genetic Variation	[5]
Pancreatic cancer	DISJC981	moderate	Biomarker	[13]
Amyotrophic lateral sclerosis	DISF7HVM	Limited	Genetic Variation	[14]
Classic lissencephaly	DISR8S3S	Limited	Biomarker	[15]
Nervous system disease	DISJ7GGT	Limited	Genetic Variation	[16]
Spinal muscular atrophy	DISTLKOB	Limited	Genetic Variation	[5]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Protein bicaudal D homolog 2 (BICD2).	[17]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Protein bicaudal D homolog 2 (BICD2).	[24]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Protein bicaudal D homolog 2 (BICD2).	[26]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Protein bicaudal D homolog 2 (BICD2).	[18]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Protein bicaudal D homolog 2 (BICD2).	[19]
Estradiol	DMUNTE3	Approved	Estradiol affects the expression of Protein bicaudal D homolog 2 (BICD2).	[20]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Protein bicaudal D homolog 2 (BICD2).	[21]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Protein bicaudal D homolog 2 (BICD2).	[22]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of Protein bicaudal D homolog 2 (BICD2).	[23]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Protein bicaudal D homolog 2 (BICD2).	[25]
Torcetrapib	DMDHYM7	Discontinued in Phase 2	Torcetrapib increases the expression of Protein bicaudal D homolog 2 (BICD2).	[27]

References

• [1] Arthrogryposis and pterygia as lethal end manifestations of genetically defined congenital myopathies.Am J Med Genet A. 2018 Feb;176(2):359-367. doi: 10.1002/ajmg.a.38577. Epub 2017 Dec 23.
• [2] The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources. Genet Med. 2022 Aug;24(8):1732-1742. doi: 10.1016/j.gim.2022.04.017. Epub 2022 May 4.
• [3] Autosomal dominant spinal muscular atrophy with lower extremity predominance: A recognizable phenotype of BICD2 mutations.Muscle Nerve. 2016 Sep;54(3):496-500. doi: 10.1002/mus.25114. Epub 2016 Jul 9.
• [4] Recurrent de novo BICD2 mutation associated with arthrogryposis multiplex congenita and bilateral perisylvian polymicrogyria.Neuromuscul Disord. 2016 Nov;26(11):744-748. doi: 10.1016/j.nmd.2016.09.009. Epub 2016 Sep 19.
• [5] BICD2 mutational analysis in hereditary spastic paraplegia and hereditary motor and sensory neuropathy.Muscle Nerve. 2019 Apr;59(4):484-486. doi: 10.1002/mus.26394. Epub 2018 Dec 21.
• [6] In-frame de novo mutation in BICD2 in two patients with muscular atrophy and arthrogryposis.Cold Spring Harb Mol Case Stud. 2018 Oct 1;4(5):a003160. doi: 10.1101/mcs.a003160. Print 2018 Oct.
• [7] Genetic and phenotypic characterisation of inherited myopathies in a tertiary neuromuscular centre.Neuromuscul Disord. 2019 Oct;29(10):747-757. doi: 10.1016/j.nmd.2019.08.003. Epub 2019 Aug 19.
• [8] Bicaudal D2 is a novel autoantibody target in systemic sclerosis that shares a key epitope with CENP-A but has a distinct clinical phenotype.Autoimmun Rev. 2018 Mar;17(3):267-275. doi: 10.1016/j.autrev.2018.01.006. Epub 2018 Jan 31.
• [9] Neuronal Roles of the Bicaudal D Family of Motor Adaptors.Vitam Horm. 2017;104:133-152. doi: 10.1016/bs.vh.2016.11.005. Epub 2016 Dec 29.
• [10] DT-13 synergistically enhanced vinorelbine-mediated mitotic arrest through inhibition of FOXM1-BICD2 axis in non-small-cell lung cancer cells.Cell Death Dis. 2017 May 25;8(5):e2810. doi: 10.1038/cddis.2017.218.
• [11] Identification of potential pathogenic genes associated with osteoporosis.Bone Joint Res. 2017 Dec;6(12):640-648. doi: 10.1302/2046-3758.612.BJR-2017-0102.R1.
• [12] Molecular defects in the motor adaptor BICD2 cause proximal spinal muscular atrophy with autosomal-dominant inheritance. Am J Hum Genet. 2013 Jun 6;92(6):955-64. doi: 10.1016/j.ajhg.2013.04.013. Epub 2013 May 9.
• [13] WITHDRAWN: MicroRNA-340 suppresses pancreatic cancer growth by targeting BICD2.Pancreatology. 2019 May 9:S1424-3903(19)30556-3. doi: 10.1016/j.pan.2019.05.453. Online ahead of print.
• [14] A novel mouse model with impaired dynein/dynactin function develops amyotrophic lateral sclerosis (ALS)-like features in motor neurons and improves lifespan in SOD1-ALS mice.Hum Mol Genet. 2008 Sep 15;17(18):2849-62. doi: 10.1093/hmg/ddn182. Epub 2008 Jun 25.
• [15] Combinatorial regulation of the balance between dynein microtubule end accumulation and initiation of directed motility.EMBO J. 2017 Nov 15;36(22):3387-3404. doi: 10.15252/embj.201797077. Epub 2017 Oct 16.
• [16] Mutations in cytoplasmic dynein and its regulators cause malformations of cortical development and neurodegenerative diseases.Biochem Soc Trans. 2013 Dec;41(6):1605-12. doi: 10.1042/BST20130188.
• [17] 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.
• [18] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [19] 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.
• [20] Identification of novel low-dose bisphenol a targets in human foreskin fibroblast cells derived from hypospadias patients. PLoS One. 2012;7(5):e36711. doi: 10.1371/journal.pone.0036711. Epub 2012 May 4.
• [21] 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.
• [22] LSD1 activates a lethal prostate cancer gene network independently of its demethylase function. Proc Natl Acad Sci U S A. 2018 May 1;115(18):E4179-E4188.
• [23] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [24] Effect of aflatoxin B(1), benzo[a]pyrene, and methapyrilene on transcriptomic and epigenetic alterations in human liver HepaRG cells. Food Chem Toxicol. 2018 Nov;121:214-223. doi: 10.1016/j.fct.2018.08.034. Epub 2018 Aug 26.
• [25] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [26] 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.
• [27] Clarifying off-target effects for torcetrapib using network pharmacology and reverse docking approach. BMC Syst Biol. 2012 Dec 10;6:152.