Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT09YVXH)

• DOT Name: Tyrosine-protein kinase ABL1 (ABL1)
• Synonyms: EC 2.7.10.2; Abelson murine leukemia viral oncogene homolog 1; Abelson tyrosine-protein kinase 1; Proto-oncogene c-Abl; p150
• Gene Name: ABL1
• Related Disease:
  Congenital heart defects and skeletal malformations syndrome
  Connective tissue disorder
• UniProt ID: ABL1_HUMAN
• PDB ID: 1AB2 ; 1AWO ; 1BBZ ; 1JU5 ; 1OPL ; 1ZZP ; 2ABL ; 2E2B ; 2F4J ; 2FO0 ; 2G1T ; 2G2F ; 2G2H ; 2G2I ; 2GQG ; 2HIW ; 2HYY ; 2HZ0 ; 2HZ4 ; 2HZI ; 2O88 ; 2V7A ; 3CS9 ; 3EG0 ; 3EG1 ; 3EG2 ; 3EG3 ; 3EGU ; 3K2M ; 3PYY ; 3QRI ; 3QRJ ; 3QRK ; 3T04 ; 3UE4 ; 3UYO ; 4J9B ; 4J9C ; 4J9D ; 4J9E ; 4J9F ; 4J9G ; 4J9H ; 4J9I ; 4JJB ; 4JJC ; 4JJD ; 4TWP ; 4WA9 ; 4XEY ; 4YC8 ; 4ZOG ; 5DC0 ; 5DC4 ; 5DC9 ; 5HU9 ; 5MO4 ; 5NP2 ; 5OAZ ; 6AMV ; 6AMW ; 6BL8 ; 6NPE ; 6NPU ; 6NPV ; 6XR6 ; 6XR7 ; 6XRG ; 7CC2 ; 7DT2 ; 7N9G ; 7PVQ ; 7PVR ; 7PVS ; 7PVV ; 7PW2 ; 7W7X ; 7W7Y ; 8H7F ; 8H7H ; 8SSN
• EC Number: 2.7.10.2
• Pfam ID: PF08919 ; PF07714 ; PF00017 ; PF00018
• Sequence:
  MLEICLKLVGCKSKKGLSSSSSCYLEEALQRPVASDFEPQGLSEAARWNSKENLLAGPSE
  NDPNLFVALYDFVASGDNTLSITKGEKLRVLGYNHNGEWCEAQTKNGQGWVPSNYITPVN
  SLEKHSWYHGPVSRNAAEYLLSSGINGSFLVRESESSPGQRSISLRYEGRVYHYRINTAS
  DGKLYVSSESRFNTLAELVHHHSTVADGLITTLHYPAPKRNKPTVYGVSPNYDKWEMERT
  DITMKHKLGGGQYGEVYEGVWKKYSLTVAVKTLKEDTMEVEEFLKEAAVMKEIKHPNLVQ
  LLGVCTREPPFYIITEFMTYGNLLDYLRECNRQEVNAVVLLYMATQISSAMEYLEKKNFI
  HRDLAARNCLVGENHLVKVADFGLSRLMTGDTYTAHAGAKFPIKWTAPESLAYNKFSIKS
  DVWAFGVLLWEIATYGMSPYPGIDLSQVYELLEKDYRMERPEGCPEKVYELMRACWQWNP
  SDRPSFAEIHQAFETMFQESSISDEVEKELGKQGVRGAVSTLLQAPELPTKTRTSRRAAE
  HRDTTDVPEMPHSKGQGESDPLDHEPAVSPLLPRKERGPPEGGLNEDERLLPKDKKTNLF
  SALIKKKKKTAPTPPKRSSSFREMDGQPERRGAGEEEGRDISNGALAFTPLDTADPAKSP
  KPSNGAGVPNGALRESGGSGFRSPHLWKKSSTLTSSRLATGEEEGGGSSSKRFLRSCSAS
  CVPHGAKDTEWRSVTLPRDLQSTGRQFDSSTFGGHKSEKPALPRKRAGENRSDQVTRGTV
  TPPPRLVKKNEEAADEVFKDIMESSPGSSPPNLTPKPLRRQVTVAPASGLPHKEEAGKGS
  ALGTPAAAEPVTPTSKAGSGAPGGTSKGPAEESRVRRHKHSSESPGRDKGKLSRLKPAPP
  PPPAASAGKAGGKPSQSPSQEAAGEAVLGAKTKATSLVDAVNSDAAKPSQPGEGLKKPVL
  PATPKPQSAKPSGTPISPAPVPSTLPSASSALAGDQPSSTAFIPLISTRVSLRKTRQPPE
  RIASGAITKGVVLDSTEALCLAISRNSEQMASHSAVLEAGKNLYTFCVSYVDSIQQMRNK
  FAFREAINKLENNLRELQICPATAGSGPAATQDFSKLLSSVKEISDIVQR
• Function: Non-receptor tyrosine-protein kinase that plays a role in many key processes linked to cell growth and survival such as cytoskeleton remodeling in response to extracellular stimuli, cell motility and adhesion, receptor endocytosis, autophagy, DNA damage response and apoptosis. Coordinates actin remodeling through tyrosine phosphorylation of proteins controlling cytoskeleton dynamics like WASF3 (involved in branch formation); ANXA1 (involved in membrane anchoring); DBN1, DBNL, CTTN, RAPH1 and ENAH (involved in signaling); or MAPT and PXN (microtubule-binding proteins). Phosphorylation of WASF3 is critical for the stimulation of lamellipodia formation and cell migration. Involved in the regulation of cell adhesion and motility through phosphorylation of key regulators of these processes such as BCAR1, CRK, CRKL, DOK1, EFS or NEDD9. Phosphorylates multiple receptor tyrosine kinases and more particularly promotes endocytosis of EGFR, facilitates the formation of neuromuscular synapses through MUSK, inhibits PDGFRB-mediated chemotaxis and modulates the endocytosis of activated B-cell receptor complexes. Other substrates which are involved in endocytosis regulation are the caveolin (CAV1) and RIN1. Moreover, ABL1 regulates the CBL family of ubiquitin ligases that drive receptor down-regulation and actin remodeling. Phosphorylation of CBL leads to increased EGFR stability. Involved in late-stage autophagy by regulating positively the trafficking and function of lysosomal components. ABL1 targets to mitochondria in response to oxidative stress and thereby mediates mitochondrial dysfunction and cell death. In response to oxidative stress, phosphorylates serine/threonine kinase PRKD2 at 'Tyr-717'. ABL1 is also translocated in the nucleus where it has DNA-binding activity and is involved in DNA-damage response and apoptosis. Many substrates are known mediators of DNA repair: DDB1, DDB2, ERCC3, ERCC6, RAD9A, RAD51, RAD52 or WRN. Activates the proapoptotic pathway when the DNA damage is too severe to be repaired. Phosphorylates TP73, a primary regulator for this type of damage-induced apoptosis. Phosphorylates the caspase CASP9 on 'Tyr-153' and regulates its processing in the apoptotic response to DNA damage. Phosphorylates PSMA7 that leads to an inhibition of proteasomal activity and cell cycle transition blocks. ABL1 acts also as a regulator of multiple pathological signaling cascades during infection. Several known tyrosine-phosphorylated microbial proteins have been identified as ABL1 substrates. This is the case of A36R of Vaccinia virus, Tir (translocated intimin receptor) of pathogenic E.coli and possibly Citrobacter, CagA (cytotoxin-associated gene A) of H.pylori, or AnkA (ankyrin repeat-containing protein A) of A.phagocytophilum. Pathogens can highjack ABL1 kinase signaling to reorganize the host actin cytoskeleton for multiple purposes, like facilitating intracellular movement and host cell exit. Finally, functions as its own regulator through autocatalytic activity as well as through phosphorylation of its inhibitor, ABI1. Regulates T-cell differentiation in a TBX21-dependent manner. Positively regulates chemokine-mediated T-cell migration, polarization, and homing to lymph nodes and immune-challenged tissues, potentially via activation of NEDD9/HEF1 and RAP1. Phosphorylates TBX21 on tyrosine residues leading to an enhancement of its transcriptional activator activity.
• Tissue Specificity: Widely expressed.
• KEGG Pathway:
  ErbB sig.ling pathway (hsa04012)
  Ras sig.ling pathway (hsa04014)
  Cell cycle (hsa04110)
  Axon guidance (hsa04360)
  Neurotrophin sig.ling pathway (hsa04722)
  Pathogenic Escherichia coli infection (hsa05130)
  Pathways in cancer (hsa05200)
  MicroR.s in cancer (hsa05206)
  Chemical carcinogenesis - reactive oxygen species (hsa05208)
  Chronic myeloid leukemia (hsa05220)
  Viral myocarditis (hsa05416)
• Reactome Pathway:
  Role of ABL in ROBO-SLIT signaling (R-HSA-428890)
  Myogenesis (R-HSA-525793)
  RHO GTPases Activate WASPs and WAVEs (R-HSA-5663213)
  HDR through Single Strand Annealing (SSA) (R-HSA-5685938)
  Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks (R-HSA-5693565)
  Cyclin D associated events in G1 (R-HSA-69231)
  RUNX1 regulates transcription of genes involved in differentiation of HSCs (R-HSA-8939236)
  RUNX2 regulates osteoblast differentiation (R-HSA-8940973)
  FCGR3A-mediated phagocytosis (R-HSA-9664422)
  Factors involved in megakaryocyte development and platelet production (R-HSA-983231)
  Regulation of actin dynamics for phagocytic cup formation (R-HSA-2029482)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Congenital heart defects and skeletal malformations syndrome	DISS72AI	Strong	Autosomal dominant	[1]
Connective tissue disorder	DISKXBS3	Moderate	Autosomal dominant	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Estradiol	DMUNTE3	Approved	Tyrosine-protein kinase ABL1 (ABL1) increases the response to substance of Estradiol.	[28]
Daunorubicin	DMQUSBT	Approved	Tyrosine-protein kinase ABL1 (ABL1) decreases the response to substance of Daunorubicin.	[29]
Hydroxyurea	DMOQVU9	Approved	Tyrosine-protein kinase ABL1 (ABL1) increases the Chronic myeloid leukaemia ADR of Hydroxyurea.	[30]
Imatinib	DM7RJXL	Approved	Tyrosine-protein kinase ABL1 (ABL1) increases the response to substance of Imatinib.	[31]
Anagrelide	DMSQ8MD	Approved	Tyrosine-protein kinase ABL1 (ABL1) increases the Thalassaemia ADR of Anagrelide.	[30]

This DOT Affected the Biotransformations of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Adenosine triphosphate	DM79F6G	Approved	Tyrosine-protein kinase ABL1 (ABL1) increases the chemical synthesis of Adenosine triphosphate.	[32]

22 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 Tyrosine-protein kinase ABL1 (ABL1).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Tyrosine-protein kinase ABL1 (ABL1).	[4]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Tyrosine-protein kinase ABL1 (ABL1).	[5]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Tyrosine-protein kinase ABL1 (ABL1).	[6]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Tyrosine-protein kinase ABL1 (ABL1).	[7]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide increases the activity of Tyrosine-protein kinase ABL1 (ABL1).	[8]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Tyrosine-protein kinase ABL1 (ABL1).	[9]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Tyrosine-protein kinase ABL1 (ABL1).	[10]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Tyrosine-protein kinase ABL1 (ABL1).	[9]
Dasatinib	DMJV2EK	Approved	Dasatinib decreases the activity of Tyrosine-protein kinase ABL1 (ABL1).	[11]
Capsaicin	DMGMF6V	Approved	Capsaicin increases the expression of Tyrosine-protein kinase ABL1 (ABL1).	[12]
Sorafenib	DMS8IFC	Approved	Sorafenib decreases the activity of Tyrosine-protein kinase ABL1 (ABL1).	[13]
Bosutinib	DMTI8YE	Approved	Bosutinib decreases the activity of Tyrosine-protein kinase ABL1 (ABL1).	[15]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone increases the expression of Tyrosine-protein kinase ABL1 (ABL1).	[17]
Belinostat	DM6OC53	Phase 2	Belinostat decreases the expression of Tyrosine-protein kinase ABL1 (ABL1).	[18]
PMID25656651-Compound-5	DMAI95U	Patented	PMID25656651-Compound-5 decreases the activity of Tyrosine-protein kinase ABL1 (ABL1).	[21]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Tyrosine-protein kinase ABL1 (ABL1).	[18]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde decreases the expression of Tyrosine-protein kinase ABL1 (ABL1).	[23]
Paraquat	DMR8O3X	Investigative	Paraquat increases the expression of Tyrosine-protein kinase ABL1 (ABL1).	[24]
Glyphosate	DM0AFY7	Investigative	Glyphosate increases the expression of Tyrosine-protein kinase ABL1 (ABL1).	[25]
MANGIFERIN	DMWAF5Z	Investigative	MANGIFERIN decreases the expression of Tyrosine-protein kinase ABL1 (ABL1).	[26]
5,6-dichloro-1-beta-D-ribofuranosylbenzimidazole	DM3JB6S	Investigative	5,6-dichloro-1-beta-D-ribofuranosylbenzimidazole decreases the expression of Tyrosine-protein kinase ABL1 (ABL1).	[27]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Nilotinib	DM7HXWT	Approved	Nilotinib decreases the phosphorylation of Tyrosine-protein kinase ABL1 (ABL1).	[14]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Tyrosine-protein kinase ABL1 (ABL1).	[19]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Tyrosine-protein kinase ABL1 (ABL1).	[20]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Tyrosine-protein kinase ABL1 (ABL1).	[22]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of Tyrosine-protein kinase ABL1 (ABL1).	[20]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Psoralen	DMIZJ8M	Phase 3	Psoralen affects the binding of Tyrosine-protein kinase ABL1 (ABL1).	[16]

References

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