Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTS7G69)

• DTT Name: Fusion protein Bcr-Abl (Bcr-Abl)
• Synonyms: BCR-ABL fusion protein; BCR-ABL
• Gene Name: BCR-ABL1
• DTT Type: Successful target; [1]
• BioChemical Class: Kinase
• UniProt ID: BCR_HUMAN-ABL1_HUMAN
• TTD ID: T38284
• Sequence:
  MVDPVGFAEAWKAQFPDSEPPRMELRSVGDIEQELERCKASIRRLEQEVNQERFRMIYLQ
  TLLAKEKKSYDRQRWGFRRAAQAPDGASEPRASASRPQPAPADGADPPPAEEPEARPDGE
  GSPGKARPGTARRPGAAASGERDDRGPPASVAALRSNFERIRKGHGQPGADAEKPFYVNV
  EFHHERGLVKVNDKEVSDRISSLGSQAMQMERKKSQHGAGSSVGDASRPPYRGRSSESSC
  GVDGDYEDAELNPRFLKDNLIDANGGSRPPWPPLEYQPYQSIYVGGMMEGEGKGPLLRSQ
  STSEQEKRLTWPRRSYSPRSFEDCGGGYTPDCSSNENLTSSEEDFSSGQSSRVSPSPTTY
  RMFRDKSRSPSQNSQQSFDSSSPPTPQCHKRHRHCPVVVSEATIVGVRKTGQIWPNDGEG
  AFHGDADGSFGTPPGYGCAADRAEEQRRHQDGLPYIDDSPSSSPHLSSKGRGSRDALVSG
  ALESTKASELDLEKGLEMRKWVLSGILASEETYLSHLEALLLPMKPLKAAATTSQPVLTS
  QQIETIFFKVPELYEIHKEFYDGLFPRVQQWSHQQRVGDLFQKLASQLGVYRAFVDNYGV
  AMEMAEKCCQANAQFAEISENLRARSNKDAKDPTTKNSLETLLYKPVDRVTRSTLVLHDL
  LKHTPASHPDHPLLQDALRISQNFLSSINEEITPRRQSMTVKKGEHRQLLKDSFMVELVE
  GARKLRHVFLFTDLLLCTKLKKQSGGKTQQYDCKWYIPLTDLSFQMVDELEAVPNIPLVP
  DEELDALKIKISQIKNDIQREKRANKGSKATERLKKKLSEQESLLLLMSPSMAFRVHSRN
  GKSYTFLISSDYERAEWRENIREQQKKCFRSFSLTSVELQMLTNSCVKLQTVHSIPLTIN
  KEDDESPGLYGFLNVIVHSATGFKQSSNLYCTLEVDSFGYFVNKAKTRVYRDTAEPNWNE
  EFEIELEGSQTLRILCYEKCYNKTKIPKEDGESTDRLMGKGQVQLDPQALQDRDWQRTVI
  AMNGIEVKLSVKFNSREFSLKRMPSRKQTGVFGVKIAVVTKRERSKVPYIVRQCVEEIER
  RGMEEVGIYRVSGVATDIQALKAAFDVNNKDVSVMMSEMDVNAIAGTLKLYFRELPEPLF
  TDEFYPNFAEGIALSDPVAKESCMLNLLLSLPEANLLTFLFLLDHLKRVAEKEAVNKMSL
  HNLATVFGPTLLRPSEKESKLPANPSQPITMTDSWSLEVMSQVQVLLYFLQLEAIPAPDS
  KRQSILFSTEVMLEICLKLVGCKSKKGLSSSSSCYLEEALQRPVASDFEPQGLSEAARWN
  SKENLLAGPSENDPNLFVALYDFVASGDNTLSITKGEKLRVLGYNHNGEWCEAQTKNGQG
  WVPSNYITPVNSLEKHSWYHGPVSRNAAEYLLSSGINGSFLVRESESSPGQRSISLRYEG
  RVYHYRINTASDGKLYVSSESRFNTLAELVHHHSTVADGLITTLHYPAPKRNKPTVYGVS
  PNYDKWEMERTDITMKHKLGGGQYGEVYEGVWKKYSLTVAVKTLKEDTMEVEEFLKEAAV
  MKEIKHPNLVQLLGVCTREPPFYIITEFMTYGNLLDYLRECNRQEVNAVVLLYMATQISS
  AMEYLEKKNFIHRDLAARNCLVGENHLVKVADFGLSRLMTGDTYTAHAGAKFPIKWTAPE
  SLAYNKFSIKSDVWAFGVLLWEIATYGMSPYPGIDLSQVYELLEKDYRMERPEGCPEKVY
  ELMRACWQWNPSDRPSFAEIHQAFETMFQESSISDEVEKELGKQGVRGAVSTLLQAPELP
  TKTRTSRRAAEHRDTTDVPEMPHSKGQGESDPLDHEPAVSPLLPRKERGPPEGGLNEDER
  LLPKDKKTNLFSALIKKKKKTAPTPPKRSSSFREMDGQPERRGAGEEEGRDISNGALAFT
  PLDTADPAKSPKPSNGAGVPNGALRESGGSGFRSPHLWKKSSTLTSSRLATGEEEGGGSS
  SKRFLRSCSASCVPHGAKDTEWRSVTLPRDLQSTGRQFDSSTFGGHKSEKPALPRKRAGE
  NRSDQVTRGTVTPPPRLVKKNEEAADEVFKDIMESSPGSSPPNLTPKPLRRQVTVAPASG
  LPHKEEAGKGSALGTPAAAEPVTPTSKAGSGAPGGTSKGPAEESRVRRHKHSSESPGRDK
  GKLSRLKPAPPPPPAASAGKAGGKPSQSPSQEAAGEAVLGAKTKATSLVDAVNSDAAKPS
  QPGEGLKKPVLPATPKPQSAKPSGTPISPAPVPSTLPSASSALAGDQPSSTAFIPLISTR
  VSLRKTRQPPERIASGAITKGVVLDSTEALCLAISRNSEQMASHSAVLEAGKNLYTFCVS
  YVDSIQQMRNKFAFREAINKLENNLRELQICPATAGSGPAATQDFSKLLSSVKEISDIVQ
  R
• Function: Activates downstream signaling pathways such as STAT5, PI3K/Akt, and Erk1/2 to lead to increased cell transformation, survival, and proliferation.

Molecular Interaction Atlas (MIA) of This DTT

4 Approved Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Asciminib	DM7EVUF	Chronic myeloid leukaemia	2A20	Approved	[2]
Dasatinib	DMJV2EK	Blast phase chronic myelogenous leukemia, BCR-ABL1 positive		Approved	[1]
Imatinib	DM7RJXL	Acute lymphoblastic leukaemia	2A85	Approved	[1]
Nilotinib	DM7HXWT	Chronic myelogenous leukaemia	2A20.0	Approved	[3]

9 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
ABL 001	DMMF5K4	Chronic myeloid leukaemia	2A20	Phase 3	[4]
ICLUSIG	DM1SQSE	Acute lymphoblastic leukaemia	2A85	Phase 3	[5]
Radotinib	DMWA74Y	leukaemia	2A60-2B33	Phase 3	[6]
AN-019	DMJ7QP8	Chronic myelogenous leukaemia	2A20.0	Phase 2	[7]
Bafetinib	DM7586F	Bone disease	FC0Z	Phase 2	[8]
HQP1351	DMQ30X2	Chronic myeloid leukaemia	2A20	Phase 2	[9]
NPB-001-056	DM78KMT	Chronic myelogenous leukaemia	2A20.0	Phase 1/2	[10]
Adaphostin	DM16QSG	Chronic myelogenous leukaemia	2A20.0	Phase 1	[11]
SCO-088	DMRD1IW	Chronic myeloid leukaemia	2A20	Phase 1	[12]

49 Patented Agent(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Aminopyrimidine derivative 1	DMK1UJV	N. A.	N. A.	Patented	[13]
Aminopyrimidine derivative 2	DMKNITP	N. A.	N. A.	Patented	[13]
Aminopyrimidine derivative 3	DMDP4GY	N. A.	N. A.	Patented	[13]
Aminopyrimidine derivative 4	DMW039D	N. A.	N. A.	Patented	[13]
Deuterated 3-cyanoquinoline derivative 1	DM3Q9OX	N. A.	N. A.	Patented	[13]
PMID25656651-Compound-10	DM8POGS	N. A.	N. A.	Patented	[13]
PMID25656651-Compound-11a	DM5ECH2	Chronic myeloid leukaemia	2A20	Patented	[13]
PMID25656651-Compound-11b	DMP580J	Chronic myeloid leukaemia	2A20	Patented	[13]
PMID25656651-Compound-11c	DMAYINQ	Chronic myeloid leukaemia	2A20	Patented	[13]
PMID25656651-Compound-15a	DM0C9YL	N. A.	N. A.	Patented	[13]
PMID25656651-Compound-15b	DMJ4DRI	N. A.	N. A.	Patented	[13]
PMID25656651-Compound-15c	DMNK2DQ	N. A.	N. A.	Patented	[13]
PMID25656651-Compound-16a	DM9XRYU	N. A.	N. A.	Patented	[13]
PMID25656651-Compound-16b	DM5EHK2	N. A.	N. A.	Patented	[13]
PMID25656651-Compound-18	DMAIVEN	N. A.	N. A.	Patented	[13]
PMID25656651-Compound-19a	DMSNUVZ	N. A.	N. A.	Patented	[13]
PMID25656651-Compound-19b	DMI1Z7D	N. A.	N. A.	Patented	[13]
PMID25656651-Compound-20a	DM7R2X0	N. A.	N. A.	Patented	[13]
PMID25656651-Compound-20b	DMLUFB2	N. A.	N. A.	Patented	[13]
PMID25656651-Compound-21a	DMCKAON	N. A.	N. A.	Patented	[13]
PMID25656651-Compound-21b	DMVABXI	N. A.	N. A.	Patented	[13]
PMID25656651-Compound-23a	DMZUB3D	N. A.	N. A.	Patented	[13]
PMID25656651-Compound-23b	DMTOFGH	N. A.	N. A.	Patented	[13]
PMID25656651-Compound-23c	DMLTR9E	N. A.	N. A.	Patented	[13]
PMID25656651-Compound-25	DMAYSNQ	N. A.	N. A.	Patented	[13]
PMID25656651-Compound-26a	DMXM98J	N. A.	N. A.	Patented	[13]
PMID25656651-Compound-26b	DMWG95Z	N. A.	N. A.	Patented	[13]
PMID25656651-Compound-26c	DMR7A58	N. A.	N. A.	Patented	[13]
PMID25656651-Compound-27	DMXK43O	N. A.	N. A.	Patented	[13]
PMID25656651-Compound-29a	DMCEST4	N. A.	N. A.	Patented	[13]
PMID25656651-Compound-29b	DMBKRY7	N. A.	N. A.	Patented	[13]
PMID25656651-Compound-30a	DMVMSQ2	N. A.	N. A.	Patented	[13]
PMID25656651-Compound-30b	DMEJMPD	N. A.	N. A.	Patented	[13]
PMID25656651-Compound-36a	DMNXVY9	N. A.	N. A.	Patented	[13]
PMID25656651-Compound-36b	DMHYDM7	N. A.	N. A.	Patented	[13]
PMID25656651-Compound-36c	DMOGKSW	N. A.	N. A.	Patented	[13]
PMID25656651-Compound-36d	DMKMY4I	N. A.	N. A.	Patented	[13]
PMID25656651-Compound-37a	DM0P4F3	N. A.	N. A.	Patented	[13]
PMID25656651-Compound-37b	DMX98YV	N. A.	N. A.	Patented	[13]
PMID25656651-Compound-37c	DM684IK	N. A.	N. A.	Patented	[13]
PMID25656651-Compound-38	DMECOY7	N. A.	N. A.	Patented	[13]
PMID25656651-Compound-40	DMLGD52	N. A.	N. A.	Patented	[13]
PMID25656651-Compound-5	DMAI95U	Chronic myeloid leukaemia	2A20	Patented	[13]
PMID25656651-Compound-7	DMK3TMD	N. A.	N. A.	Patented	[13]
Pyridoindole derivative 1	DMP6TUQ	N. A.	N. A.	Patented	[13]
Pyridoindole derivative 2	DMIXK7Y	N. A.	N. A.	Patented	[13]
Pyridoindole derivative 3	DMONCT1	N. A.	N. A.	Patented	[13]
Pyrimidinyl pyrazolamine derivative 1	DM72T58	N. A.	N. A.	Patented	[13]
Pyrrolo[2,3-b]pyridine carboxamide derivative 1	DMWXZBF	N. A.	N. A.	Patented	[13]

7 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
(E)-4-(3,5-dimethoxystyryl)phenol	DMYXI2V	Discovery agent	N.A.	Investigative	[14]
3'',5''-dimethoxy-[1,1':2',1'']-terphenyl-4-ol	DMRY2ZC	Discovery agent	N.A.	Investigative	[14]
3'',5''-dimethoxy-[1,1':3',1'']-terphenyl-4-ol	DMXCZAK	Discovery agent	N.A.	Investigative	[14]
4,3'',5''-trimethoxy-[1,1':2',1'']-terphenyl	DMBN4G6	Discovery agent	N.A.	Investigative	[14]
4,3'',5''-trimethoxy-[1,1':3',1'']-terphenyl	DM40E1T	Discovery agent	N.A.	Investigative	[14]
HKI-9924129	DM5LR2B	Gram-positive bacterial infection	1B74-1G40	Investigative	[15]
PD-0173955	DMOZEW9	Discovery agent	N.A.	Investigative	[16]

References

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• [2] Asciminib in Chronic Myeloid Leukemia after ABL Kinase Inhibitor Failure. N Engl J Med. 2019 Dec 12;381(24):2315-2326.
• [3] 2007 FDA drug approvals: a year of flux. Nat Rev Drug Discov. 2008 Feb;7(2):107-9.
• [4] ABL001, a Potent Allosteric Inhibitor of BCR-ABL, Prevents Emergence of Resistant Disease When Administered in Combination with Nilotinib in an in Vivo Murine Model of Chronic Myeloid Leukemia, NorthBuilding, 2014, 120-125.
• [5] Ponatinib efficacy and safety in Philadelphia chromosome-positive leukemia: final 5-year results of the phase 2 PACE trial. Blood. 2018 Jul 26;132(4):393-404.
• [6] Danusertib, an aurora kinase inhibitor.Expert Opin Investig Drugs.2012 Mar;21(3):383-93.
• [7] Design, synthesis and preclinical evaluation of NRC-AN-019. Int J Oncol. 2013 Jan;42(1):168-78.
• [8] Interpreting expression profiles of cancers by genome-wide survey of breadth of expression in normal tissues. Genomics 2005 Aug;86(2):127-41.
• [9] Preclinical development of HQP1351, a multikinase inhibitor targeting a broad spectrum of mutant KIT kinases, for the treatment of imatinib-resistant gastrointestinal stromal tumors. Cell Biosci. 2019 Oct 26;9:88.
• [10] NPB001-05 inhibits Bcr-Abl kinase leading to apoptosis of imatinib-resistant cells. Front Biosci (Elite Ed). 2011 Jun 1;3:1273-88.
• [11] Effects of the Bcr/abl kinase inhibitors STI571 and adaphostin (NSC 680410) on chronic myelogenous leukemia cells in vitro. Blood. 2002 Jan 15;99(2):664-71.
• [12] Clinical pipeline report, company report or official report of Sun Pharma Advanced Research Company.
• [13] Bcr-Abl tyrosine kinase inhibitors: a patent review.Expert Opin Ther Pat. 2015 Apr;25(4):397-412.
• [14] 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.
• [15] Activity of the Bcr-Abl kinase inhibitor PD180970 against clinically relevant Bcr-Abl isoforms that cause resistance to imatinib mesylate (Gleevec, STI571). Cancer Res. 2002 Dec 15;62(24):7149-53.
• [16] Structural insights into the ATP binding pocket of the anaplastic lymphoma kinase by site-directed mutagenesis, inhibitor binding analysis, and hom... J Med Chem. 2006 Sep 21;49(19):5759-68.