Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TT6B75U)

• DTT Name: ABL messenger RNA (ABL mRNA)
• Synonyms: p150 (mRNA); Proto-oncogene tyrosine-protein kinase ABL1 (mRNA); Proto-oncogene c-Abl (mRNA); JTK7 (mRNA); C-ABL (mRNA); Abl (mRNA); Abelson tyrosine-protein kinase 1 (mRNA); Abelson murine leukemia viral oncogene homolog 1 (mRNA)
• Gene Name: ABL1
• DTT Type: Discontinued target; [1]
• BioChemical Class: mRNA target
• UniProt ID: ABL1_HUMAN
• TTD ID: T89747
• EC Number: EC 2.7.10.2
• Sequence:
  MLEICLKLVGCKSKKGLSSSSSCYLEEALQRPVASDFEPQGLSEAARWNSKENLLAGPSE
  NDPNLFVALYDFVASGDNTLSITKGEKLRVLGYNHNGEWCEAQTKNGQGWVPSNYITPVN
  SLEKHSWYHGPVSRNAAEYLLSSGINGSFLVRESESSPGQRSISLRYEGRVYHYRINTAS
  DGKLYVSSESRFNTLAELVHHHSTVADGLITTLHYPAPKRNKPTVYGVSPNYDKWEMERT
  DITMKHKLGGGQYGEVYEGVWKKYSLTVAVKTLKEDTMEVEEFLKEAAVMKEIKHPNLVQ
  LLGVCTREPPFYIITEFMTYGNLLDYLRECNRQEVNAVVLLYMATQISSAMEYLEKKNFI
  HRDLAARNCLVGENHLVKVADFGLSRLMTGDTYTAHAGAKFPIKWTAPESLAYNKFSIKS
  DVWAFGVLLWEIATYGMSPYPGIDLSQVYELLEKDYRMERPEGCPEKVYELMRACWQWNP
  SDRPSFAEIHQAFETMFQESSISDEVEKELGKQGVRGAVSTLLQAPELPTKTRTSRRAAE
  HRDTTDVPEMPHSKGQGESDPLDHEPAVSPLLPRKERGPPEGGLNEDERLLPKDKKTNLF
  SALIKKKKKTAPTPPKRSSSFREMDGQPERRGAGEEEGRDISNGALAFTPLDTADPAKSP
  KPSNGAGVPNGALRESGGSGFRSPHLWKKSSTLTSSRLATGEEEGGGSSSKRFLRSCSAS
  CVPHGAKDTEWRSVTLPRDLQSTGRQFDSSTFGGHKSEKPALPRKRAGENRSDQVTRGTV
  TPPPRLVKKNEEAADEVFKDIMESSPGSSPPNLTPKPLRRQVTVAPASGLPHKEEAGKGS
  ALGTPAAAEPVTPTSKAGSGAPGGTSKGPAEESRVRRHKHSSESPGRDKGKLSRLKPAPP
  PPPAASAGKAGGKPSQSPSQEAAGEAVLGAKTKATSLVDAVNSDAAKPSQPGEGLKKPVL
  PATPKPQSAKPSGTPISPAPVPSTLPSASSALAGDQPSSTAFIPLISTRVSLRKTRQPPE
  RIASGAITKGVVLDSTEALCLAISRNSEQMASHSAVLEAGKNLYTFCVSYVDSIQQMRNK
  FAFREAINKLENNLRELQICPATAGSGPAATQDFSKLLSSVKEISDIVQR
• Function: 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. Phosphorylates TBX21 on tyrosine residues leading to an enhancement of its transcriptional activator activity. 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.
• KEGG Pathway:
  ErbB signaling pathway (hsa04012)
  Ras signaling pathway (hsa04014)
  Cell cycle (hsa04110)
  Axon guidance (hsa04360)
  Neurotrophin signaling pathway (hsa04722)
  Pathogenic Escherichia coli infection (hsa05130)
  Shigellosis (hsa05131)
  Pathways in cancer (hsa05200)
  MicroRNAs in cancer (hsa05206)
  Chronic myeloid leukemia (hsa05220)
  Viral myocarditis (hsa05416)
• Reactome Pathway:
  CDO in myogenesis (R-HSA-375170)
  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)
  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 DTT

1 Discontinued Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
G-1128	DMHOMFK	Chronic myelogenous leukaemia	2A20.0	Discontinued in Phase 2	[1]

5 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
GNF-5	DMGLIPV	Discovery agent	N.A.	Investigative	[2]
PMID21561767C8h	DMABZH6	Discovery agent	N.A.	Investigative	[3]
PMID23441572C24	DMG4MLA	Discovery agent	N.A.	Investigative	[4]
PMID24900538C2c	DM5PATM	Discovery agent	N.A.	Investigative	[5]
PP121	DMU8KTO	Discovery agent	N.A.	Investigative	[6]

References

• [1] Pharmaceutical Design And Development: A Molecular Biology Approach, T V Ramabhadran, 2005. Page(219).
• [2] Targeting Bcr-Abl by combining allosteric with ATP-binding-site inhibitors. Nature. 2010 Jan 28;463(7280):501-6.
• [3] Discovery of 5-(arenethynyl) hetero-monocyclic derivatives as potent inhibitors of BCR-ABL including the T315I gatekeeper mutant. Bioorg Med Chem Lett. 2011 Jun 15;21(12):3743-8.
• [4] Rapid discovery of a novel series of Abl kinase inhibitors by application of an integrated microfluidic synthesis and screening platform. J Med Chem. 2013 Apr 11;56(7):3033-47.
• [5] Discovery of Disubstituted Imidazo[4,5-b]pyridines and Purines as Potent TrkA Inhibitors. ACS Med Chem Lett. 2012 Jul 26;3(9):705-9.
• [6] Targeted polypharmacology: discovery of dual inhibitors of tyrosine and phosphoinositide kinases. Nat Chem Biol. 2008 Nov;4(11):691-9.