Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TT3PJMV)

• DTT Name: Tyrosine-protein kinase ABL1 (ABL)
• Synonyms: p150; Proto-oncogene tyrosine-protein kinase ABL1; Proto-oncogene c-Abl; JTK7; C-ABL; Abl; Abelson tyrosine-protein kinase 1; Abelson murine leukemia viral oncogene homolog 1
• Gene Name: ABL1
• DTT Type: Successful target; [1]
• Related Disease:
  Breast cancer [ICD-11: 2C60-2C6Y]
  Ischemia [ICD-11: 8B10-8B11]
  Mature B-cell lymphoma [ICD-11: 2A85]
  Nutritional deficiency [ICD-11: 5B50-5B71]
• BioChemical Class: Kinase
• UniProt ID: ABL1_HUMAN
• TTD ID: T63505
• 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

4 Approved Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Adenosine triphosphate	DM79F6G	Malnutrition	5B50-5B71	Approved	[1], [2]
Bosutinib	DMTI8YE	Breast cancer	2C60-2C65	Approved	[3]
Ponatinib	DMYGJQO	Acute lymphoblastic leukaemia	2A85	Approved	[4]
SKI-758	DMQ8E9R	Ischemia	8B10-8B11	Approved	[5]

5 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Flumatinib	DM0G5O6	Chronic myelogenous leukaemia	2A20.0	Phase 2	[6]
Saracatinib	DMBLHGP	Hematologic tumour	2B33.Y	Phase 2	[7]
DCC-2036	DMJKFNU	Chronic myeloid leukaemia	2A20	Phase 1/2	[8]
ISIS-CRP	DMQDUG4	Cardiovascular disease	BA00-BE2Z	Phase 1	[9]
KW-2449	DMFO7RP	Acute myeloid leukaemia	2A60	Phase 1	[10]

17 Patented Agent(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
6,6-fused nitrogenous heterocyclic compound 1	DM0VEBI	N. A.	N. A.	Patented	[11]
6,6-fused nitrogenous heterocyclic compound 2	DMB1EAW	N. A.	N. A.	Patented	[11]
6,6-fused nitrogenous heterocyclic compound 3	DMX3VCO	N. A.	N. A.	Patented	[11]
Azaindole derivative 1	DMSMXK3	N. A.	N. A.	Patented	[11]
Azaindole derivative 2	DMXBYHV	N. A.	N. A.	Patented	[11]
Indol-5-ol derivative 1	DM5F8J1	N. A.	N. A.	Patented	[11]
PMID25656651-Compound-28a	DM06LDV	N. A.	N. A.	Patented	[11]
PMID25656651-Compound-28b	DMKB7XV	N. A.	N. A.	Patented	[11]
PMID25656651-Compound-33a	DMCRA2U	N. A.	N. A.	Patented	[11]
PMID25656651-Compound-33b	DMU8ZI3	N. A.	N. A.	Patented	[11]
PMID25656651-Compound-34a	DMWOR8B	N. A.	N. A.	Patented	[11]
PMID25656651-Compound-34b	DMBD706	N. A.	N. A.	Patented	[11]
PMID25656651-Compound-34c	DMG5I41	N. A.	N. A.	Patented	[11]
PMID25656651-Compound-42	DMTUA6E	N. A.	N. A.	Patented	[11]
PMID25656651-Compound-46	DM7XQUT	N. A.	N. A.	Patented	[11]
PMID27774824-Compound-Figure9Example2down	DMXAV42	N. A.	N. A.	Patented	[12]
PMID27774824-Compound-Figure9Example2up	DME3TMS	N. A.	N. A.	Patented	[12]

1 Preclinical Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
MC-2001	DMBT2RJ	leukaemia	2A60-2B33	Preclinical	[13]

18 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
4-[(3,5-diamino-1H-pyrazol-4-yl)diazenyl]phenol	DMSKJ1X	Discovery agent	N.A.	Investigative	[14]
AP-24226	DMGTEXD	Discovery agent	N.A.	Investigative	[15]
BAS-00387275	DMZPKGS	Discovery agent	N.A.	Investigative	[16]
BAS-00387328	DM4OSFD	Discovery agent	N.A.	Investigative	[16]
BAS-00387347	DMUF28Q	Discovery agent	N.A.	Investigative	[16]
BAS-00672722	DM6R4X8	Discovery agent	N.A.	Investigative	[16]
BAS-01373578	DMZBIC3	Discovery agent	N.A.	Investigative	[16]
BAS-0338872	DMZK0SC	Discovery agent	N.A.	Investigative	[17]
BAS-0338876	DMBS8N9	Discovery agent	N.A.	Investigative	[17]
BAS-09534324	DMFMBZ9	Discovery agent	N.A.	Investigative	[16]
Bis-(5-hydroxy-1H-indol-2-yl)-methanone	DMTSEXB	Discovery agent	N.A.	Investigative	[18]
JNJ-10198409	DM9GDP5	Discovery agent	N.A.	Investigative	[19]
MYRISTIC ACID	DMYX0BL	Discovery agent	N.A.	Investigative	[20]
PD-0166326	DMD2CG9	Discovery agent	N.A.	Investigative	[21]
PD-0173956	DM8RW92	Discovery agent	N.A.	Investigative	[21]
TG-100435	DMIR3X2	Discovery agent	N.A.	Investigative	[22]
TRISMETHOXYRESVERATROL	DM6USPC	Discovery agent	N.A.	Investigative	[23]
[1,1':2',1'']-terphenyl-4,3'',5''-triol	DMVOY4D	Discovery agent	N.A.	Investigative	[23]

Molecular Expression Atlas (MEA) of This DTT

Disease Name	ICD 11	Studied Tissue	p-value	Fold-Change	Z-score
Multiple myeloma	2C82	Bone marrow	6.28E-04	0.33	2.07
Acute myelocytic leukaemia	2C82	Bone marrow	9.65E-34	0.48	1.49
Prostate cancer	2C82	Prostate	2.14E-05	-0.34	-0.82
Breast cancer	2C82	Breast tissue	1.24E-35	-0.35	-0.84
Sarcoma	2C82	Muscle tissue	6.32E-253	1.6	3.15

References

• [1] Targeted chronic myeloid leukemia therapy: Seeking a cure. Am J Health Syst Pharm. 2007 Dec 15;64(24 Suppl 15):S9-15.
• [2] High frequency of point mutations clustered within the adenosine triphosphate-binding region of BCR/ABL in patients with chronic myeloid leukemia or Ph-positive acute lymphoblastic leukemia who develop imatinib (STI571) resistance. Blood. 2002 May 1;99(9):3472-5.
• [3] A comparison of physicochemical property profiles of marketed oral drugs and orally bioavailable anti-cancer protein kinase inhibitors in clinical development. Curr Top Med Chem. 2007;7(14):1408-22.
• [4] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
• [5] Synthesis and Src kinase inhibitory activity of a series of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-7-furyl-3-quinolinecarbonitriles. J Med Chem. 2006 Dec 28;49(26):7868-76.
• [6] Flumatinib, a selective inhibitor of BCR-ABL/PDGFR/KIT, effectively overcomes drug resistance of certain KIT mutants. Cancer Sci. 2014 Jan;105(1):117-25.
• [7] Novel dual Src/Abl inhibitors for hematologic and solid malignancies.Expert Opin Investig Drugs.2010 Aug;19(8):931-45.
• [8] Company report (Deciphera Pharmaceuticals: Tumor-Targeted Programs and Indications)
• [9] Structure-based optimization of pyrazolo[3,4-d]pyrimidines as Abl inhibitors and antiproliferative agents toward human leukemia cell lines. J Med Chem. 2008 Mar 13;51(5):1252-9.
• [10] KW-2449, a novel multikinase inhibitor, suppresses the growth of leukemia cells with FLT3 mutations or T315I-mutated BCR/ABL translocation. Blood. 2009 Aug 20;114(8):1607-17.
• [11] Bcr-Abl tyrosine kinase inhibitors: a patent review.Expert Opin Ther Pat. 2015 Apr;25(4):397-412.
• [12] Inhibitors of JAK-family kinases: an update on the patent literature 2013-2015, part 1.Expert Opin Ther Pat. 2017 Feb;27(2):127-143.
• [13] Vascular endothelial growth factor and its receptors in multiple myeloma. Leukemia. 2003 Oct;17(10):1961-6.
• [14] 4-arylazo-3,5-diamino-1H-pyrazole CDK inhibitors: SAR study, crystal structure in complex with CDK2, selectivity, and cellular effects. J Med Chem. 2006 Nov 2;49(22):6500-9.
• [15] Discovery of 3-[2-(imidazo[1,2-b]pyridazin-3-yl)ethynyl]-4-methyl-N-{4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl}benzamide (AP2453... J Med Chem. 2010 Jun 24;53(12):4701-19.
• [16] A combination of docking/dynamics simulations and pharmacophoric modeling to discover new dual c-Src/Abl kinase inhibitors. J Med Chem. 2006 Jun 1;49(11):3278-86.
• [17] Discovery and SAR of 1,3,4-thiadiazole derivatives as potent Abl tyrosine kinase inhibitors and cytodifferentiating agents. Bioorg Med Chem Lett. 2008 Feb 1;18(3):1207-11.
• [18] Novel bis(1H-indol-2-yl)methanones as potent inhibitors of FLT3 and platelet-derived growth factor receptor tyrosine kinase. J Med Chem. 2006 Jun 1;49(11):3101-15.
• [19] (6,7-Dimethoxy-2,4-dihydroindeno[1,2-c]pyrazol-3-yl)phenylamines: platelet-derived growth factor receptor tyrosine kinase inhibitors with broad ant... J Med Chem. 2005 Dec 29;48(26):8163-73.
• [20] The Protein Data Bank. Nucleic Acids Res. 2000 Jan 1;28(1):235-42.
• [21] Structure-activity relationships of 6-(2,6-dichlorophenyl)-8-methyl-2-(phenylamino)pyrido[2,3-d]pyrimidin-7-ones: toward selective Abl inhibitors. Bioorg Med Chem Lett. 2009 Dec 15;19(24):6872-6.
• [22] Discovery of [7-(2,6-dichlorophenyl)-5-methylbenzo [1,2,4]triazin-3-yl]-[4-(2-pyrrolidin-1-ylethoxy)phenyl]amine--a potent, orally active Src kinas... Bioorg Med Chem Lett. 2007 Feb 1;17(3):602-8.
• [23] Identification of a terphenyl derivative that blocks the cell cycle in the G0-G1 phase and induces differentiation in leukemia cells. J Med Chem. 2006 May 18;49(10):3012-8.