Drug Information

Drug (ID: DG00358) and It's Reported Resistant Information
Name
Tyrosine kinase inhibitor
Synonyms
Tyrosine kinase inhibitor; 1021950-26-4; 1-N'-(4-fluorophenyl)-1-N-[4-[[2-(2-morpholin-4-ylethylcarbamoyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxy]phenyl]cyclopropane-1,1-dicarboxamide; SCHEMBL10108314; C31H31FN6O5; DTXSID40648066; BCP04781; EX-A2282; MDK-0264; 4136AH; NSC757436; ZINC43195804; CS-0524; NSC-757436; NCGC00390567-01; HY-10421; DB-058774; FT-0753909; EC-000.2366; 1,1-Cyclopropanedicarboxamide, N-(4-fluorophenyl)-N-[4-[[2-[[[2-(4-morpholinyl)ethyl]amino]carbonyl]-1H-pyrrolo[2,3-b]pyridin-4-yl]oxy]phenyl]-; N'1-(4-fluorophenyl)-N1-{4-[(2-{[2-(morpholin-4-yl)ethyl]carbamoyl}-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]phenyl}cyclopropane-1,1-dicarboxamide; N~1~-(4-Fluorophenyl)-N'~1~-{4-[(2-{[2-(morpholin-4-yl)ethyl]carbamoyl}-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]phenyl}cyclopropane-1,1-dicarboxamide
    Click to Show/Hide
Structure
Drug Resistance Disease(s)
Disease(s) with Clinically Reported Resistance for This Drug (2 diseases)
Acute myeloid leukemia [ICD-11: 2A60]
[1]
Chronic myeloid leukemia [ICD-11: 2A20]
[2], [3]
Click to Show/Hide the Molecular Information and External Link(s) of This Drug
Formula
C31H31FN6O5
IsoSMILES
C1CC1(C(=O)NC2=CC=C(C=C2)OC3=C4C=C(NC4=NC=C3)C(=O)NCCN5CCOCC5)C(=O)NC6=CC=C(C=C6)F
InChI
1S/C31H31FN6O5/c32-20-1-3-21(4-2-20)35-29(40)31(10-11-31)30(41)36-22-5-7-23(8-6-22)43-26-9-12-33-27-24(26)19-25(37-27)28(39)34-13-14-38-15-17-42-18-16-38/h1-9,12,19H,10-11,13-18H2,(H,33,37)(H,34,39)(H,35,40)(H,36,41)
InChIKey
PKOVTRMHYNEBDU-UHFFFAOYSA-N
PubChem CID
24956525
Type(s) of Resistant Mechanism of This Drug due to Structure Alteration
  ADTT: Aberration of the Drug's Therapeutic Target
Drug Resistance Data Categorized by Their Corresponding Diseases
ICD-02: Benign/in-situ/malignant neoplasm
Click to Show/Hide the Resistance Disease of This Class
Chronic myeloid leukemia [ICD-11: 2A20]
Click to Show/Hide
Drug Resistance Data Categorized by Their Corresponding Mechanisms
  Aberration of the Drug's Therapeutic Target (ADTT) Click to Show/Hide
Key Molecule: Tyrosine-protein kinase ABL1 (ABL1) [3]
Resistant Disease Chronic myeloid leukemia [ICD-11: 2A20.0]
 Disease Info 
Molecule Alteration Missense mutation
p.T315I
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 2.89  Å
PDB: 4XEY
Mutant Type Structure Method: X-ray diffraction Resolution: 2.17  Å
PDB: 5MO4
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.69
TM score: 0.88225
Amino acid change:
T315I
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
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Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
Mechanism Description There are several identified mechanisms of resistance to TkIs. The presence of ABL kinase domain point mutation, which could be detected by molecular methods is one of them. ABL mutation was detected in 19 (31,6%) patients. In four cases with detected mutation the disease has progressed to blast crisis.
Key Molecule: Tyrosine-protein kinase ABL1 (ABL1) [3]
Resistant Disease Chronic myeloid leukemia [ICD-11: 2A20.0]
 Disease Info 
Molecule Alteration Missense mutation
p.G250E
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 2.17  Å
PDB: 5MO4
Mutant Type Structure Method: Solution NMR Resolution: N.A.
PDB: 6XRG
   Download The Information of Sequence       Download The Structure File   
RMSD: 2.4
TM score: 0.79586
Amino acid change:
G250E
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
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S
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A
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540
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I
I
S
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D
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E
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V
E
E
K
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G
G
550
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K
K
Q
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G
G
V
V
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
Mechanism Description There are several identified mechanisms of resistance to TkIs. The presence of ABL kinase domain point mutation, which could be detected by molecular methods is one of them. ABL mutation was detected in 19 (31,6%) patients. In four cases with detected mutation the disease has progressed to blast crisis.
References
Ref 1 Genomic Profiling of Pediatric Acute Myeloid Leukemia Reveals a Changing Mutational Landscape from Disease Diagnosis to Relapse. Cancer Res. 2016 Apr 15;76(8):2197-205. doi: 10.1158/0008-5472.CAN-15-1015. Epub 2016 Mar 3.
Ref 2 Longitudinal studies of SRC family kinases in imatinib- and dasatinib-resistant chronic myelogenous leukemia patients. Leuk Res. 2011 Jan;35(1):38-43. doi: 10.1016/j.leukres.2010.06.030. Epub 2010 Jul 29.
Ref 3 [ABL domain kinase point mutations as a cause of resistance to therapy of patients with chronic myeloid leukemia with tyrosine kinase inhibitors. Single center experience]. Przegl Lek. 2011;68(5):253-7.

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