Drug Information

Drug (ID: DG01652) and It's Reported Resistant Information
Name
PRN1371
Synonyms
PRN1371; 1802929-43-6; PRN-1371; 8-(3-(4-acryloylpiperazin-1-yl)propyl)-6-(2,6-dichloro-3,5-dimethoxyphenyl)-2-(methylamino)pyrido[2,3-d]pyrimidin-7(8H)-one; UNII-S3OPE9IA3Q; S3OPE9IA3Q; 6-(2,6-dichloro-3,5-dimethoxyphenyl)-2-(methylamino)-8-[3-(4-prop-2-enoylpiperazin-1-yl)propyl]pyrido[2,3-d]pyrimidin-7-one; GTPL9788; CHEMBL4068509; SCHEMBL16993012; US9567334, Example 6; BDBM286984; BCP20493; EX-A2927; NSC801089; s8578; CCG-270053; CS-7485; NSC-801089; compound 34 [PMID: 28665128]; BP179867; HY-101768; J3.662.238E; C92492; A936037; Q29213602
    Click to Show/Hide
Indication
In total 3 Indication(s)
Gastrointestinal stromal tumour [ICD-11: 2B5B]
Phase 1
[1]
Mast cell leukaemia [ICD-11: 2A21]
Phase 1
[1]
Systemic mastocytosis [ICD-11: 2A21]
Phase 1
[1]
Structure
Target Platelet-derived growth factor receptor alpha (PDGFRA) PGFRA_HUMAN [1]
Click to Show/Hide the Molecular Information and External Link(s) of This Drug
Formula
9
IsoSMILES
CNC1=NC=C2C=C(C(=O)N(C2=N1)CCCN3CCN(CC3)C(=O)C=C)C4=C(C(=CC(=C4Cl)OC)OC)Cl
InChI
InChI=1S/C26H30Cl2N6O4/c1-5-20(35)33-11-9-32(10-12-33)7-6-8-34-24-16(15-30-26(29-2)31-24)13-17(25(34)36)21-22(27)18(37-3)14-19(38-4)23(21)28/h5,13-15H,1,6-12H2,2-4H3,(H,29,30,31)
InChIKey
PUIXMSRTTHLNKI-UHFFFAOYSA-N
PubChem CID
118295624
TTD Drug ID
D0UO2P
Type(s) of Resistant Mechanism of This Drug
  UAPP: Unusual Activation of Pro-survival Pathway
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
Solid tumour/cancer [ICD-11: 2A00-2F9Z]
Click to Show/Hide
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: Fibroblast growth factor receptor 1 (FGFR1) [1]
Sensitive Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
 Disease Info 
Molecule Alteration Missense mutation
p.V561M (c.1681G>A)
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 1.63  Å
PDB: 5EW8
Mutant Type Structure Method: X-ray diffraction Resolution: 1.96  Å
PDB: 5AM7
   Download The Information of Sequence       Download The Structure File   
RMSD: 0.32
TM score: 0.98379
Amino acid change:
V561M
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
-
M
G
V
A
A
G
G
460
|
V
V
S
S
E
E
Y
Y
E
E
L
L
P
P
E
E
D
D
P
P
470
|
R
R
W
W
E
E
L
L
P
P
R
R
D
D
R
R
L
L
V
V
480
|
L
L
G
G
K
K
P
P
L
L
G
G
E
E
G
G
A
A
F
F
490
|
G
G
Q
Q
V
V
V
V
L
L
A
A
E
E
A
A
I
I
G
G
500
|
L
L
D
D
K
K
D
D
K
K
P
P
N
N
R
R
V
V
T
T
510
|
K
K
V
V
A
A
V
V
K
K
M
M
L
L
K
K
S
S
D
D
520
|
A
A
T
T
E
E
K
K
D
D
L
L
S
S
D
D
L
L
I
I
530
|
S
S
E
E
M
M
E
E
M
M
M
M
K
K
M
M
I
I
G
G
540
|
K
K
H
H
K
K
N
N
I
I
I
I
N
N
L
L
L
L
G
G
550
|
A
A
C
C
T
T
Q
Q
D
D
G
G
P
P
L
L
Y
Y
V
V
560
|
I
I
V
M
E
E
Y
Y
A
A
S
S
K
K
G
G
N
N
L
L
570
|
R
R
E
E
Y
Y
L
L
Q
Q
A
A
R
R
R
R
P
P
P
P
580
|
G
G
L
L
E
E
Y
Y
S
S
Y
Y
N
N
P
P
S
S
H
H
590
|
N
N
P
P
E
E
E
E
Q
Q
L
L
S
S
S
S
K
K
D
D
600
|
L
L
V
V
S
S
C
C
A
A
Y
Y
Q
Q
V
V
A
A
R
R
610
|
G
G
M
M
E
E
Y
Y
L
L
A
A
S
S
K
K
K
K
C
C
620
|
I
I
H
H
R
R
D
D
L
L
A
A
A
A
R
R
N
N
V
V
630
|
L
L
V
V
T
T
E
E
D
D
N
N
V
V
M
M
K
K
I
I
640
|
A
A
D
D
F
F
G
G
L
L
A
A
R
R
D
D
I
I
H
H
650
|
H
H
I
I
D
D
Y
Y
Y
Y
K
K
K
K
T
T
T
T
N
N
660
|
G
G
R
R
L
L
P
P
V
V
K
K
W
W
M
M
A
A
P
P
670
|
E
E
A
A
L
L
F
F
D
D
R
R
I
I
Y
Y
T
T
H
H
680
|
Q
Q
S
S
D
D
V
V
W
W
S
S
F
F
G
G
V
V
L
L
690
|
L
L
W
W
E
E
I
I
F
F
T
T
L
L
G
G
G
G
S
S
700
|
P
P
Y
Y
P
P
G
G
V
V
P
P
V
V
E
E
E
E
L
L
710
|
F
F
K
K
L
L
L
L
K
K
E
E
G
G
H
H
R
R
M
M
720
|
D
D
K
K
P
P
S
S
N
N
C
C
T
T
N
N
E
E
L
L
730
|
Y
Y
M
M
M
M
M
M
R
R
D
D
C
C
W
W
H
H
A
A
740
|
V
V
P
P
S
S
Q
Q
R
R
P
P
T
T
F
F
K
K
Q
Q
750
|
L
L
V
V
E
E
D
D
L
L
D
D
R
R
I
I
V
V
A
A
760
|
L
L
T
T
S
S
N
N
Q
Q
E
E
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation FGF/FGFR signaling pathway Inhibition hsa01521
In Vitro Model HCT116 cells Colon Homo sapiens (Human) CVCL_0291
Hep3B cells Liver Homo sapiens (Human) CVCL_0326
RT4 cells Bladder Homo sapiens (Human) CVCL_0036
NCI-H716 cells Colon Homo sapiens (Human) CVCL_1581
RT112 cells Bladder Homo sapiens (Human) CVCL_1670
AN3CA cells Ovary Homo sapiens (Human) CVCL_0028
Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
SNU878 cells Liver Homo sapiens (Human) CVCL_5102
SNU16 cells Ascites Homo sapiens (Human) CVCL_0076
OPM2 cells Peripheral blood Homo sapiens (Human) CVCL_1625
LI7 cells Liver Homo sapiens (Human) CVCL_3840
JHH7 cells Liver Homo sapiens (Human) CVCL_2805
In Vivo Model Nude mouse PDX model Mus musculus
Experiment for
Drug Resistance		 Promega assay
Mechanism Description PRN1371 exhibits potent and durable pathway inhibition, and robust antiproliferative activity. PRN1371 demonstrates prolonged FGFR inhibition in vivo.
Key Molecule: Fibroblast growth factor receptor 2 (FGFR2) [1]
Sensitive Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
 Disease Info 
Molecule Alteration Missense mutation
p.N550K (c.1650T>G)
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation FGF/FGFR signaling pathway Inhibition hsa01521
In Vitro Model HCT116 cells Colon Homo sapiens (Human) CVCL_0291
Hep3B cells Liver Homo sapiens (Human) CVCL_0326
RT4 cells Bladder Homo sapiens (Human) CVCL_0036
NCI-H716 cells Colon Homo sapiens (Human) CVCL_1581
RT112 cells Bladder Homo sapiens (Human) CVCL_1670
AN3CA cells Ovary Homo sapiens (Human) CVCL_0028
Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
SNU878 cells Liver Homo sapiens (Human) CVCL_5102
SNU16 cells Ascites Homo sapiens (Human) CVCL_0076
OPM2 cells Peripheral blood Homo sapiens (Human) CVCL_1625
LI7 cells Liver Homo sapiens (Human) CVCL_3840
JHH7 cells Liver Homo sapiens (Human) CVCL_2805
In Vivo Model Nude mouse PDX model Mus musculus
Experiment for
Drug Resistance		 Promega assay
Mechanism Description PRN1371 exhibits potent and durable pathway inhibition, and robust antiproliferative activity. PRN1371 demonstrates prolonged FGFR inhibition in vivo.
Key Molecule: Fibroblast growth factor receptor 2 (FGFR2) [1]
Sensitive Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
 Disease Info 
Molecule Alteration Missense mutation
p.K660E (c.1978A>G)
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation FGF/FGFR signaling pathway Inhibition hsa01521
In Vitro Model HCT116 cells Colon Homo sapiens (Human) CVCL_0291
Hep3B cells Liver Homo sapiens (Human) CVCL_0326
RT4 cells Bladder Homo sapiens (Human) CVCL_0036
NCI-H716 cells Colon Homo sapiens (Human) CVCL_1581
RT112 cells Bladder Homo sapiens (Human) CVCL_1670
AN3CA cells Ovary Homo sapiens (Human) CVCL_0028
Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
SNU878 cells Liver Homo sapiens (Human) CVCL_5102
SNU16 cells Ascites Homo sapiens (Human) CVCL_0076
OPM2 cells Peripheral blood Homo sapiens (Human) CVCL_1625
LI7 cells Liver Homo sapiens (Human) CVCL_3840
JHH7 cells Liver Homo sapiens (Human) CVCL_2805
In Vivo Model Nude mouse PDX model Mus musculus
Experiment for
Drug Resistance		 Promega assay
Mechanism Description PRN1371 exhibits potent and durable pathway inhibition, and robust antiproliferative activity. PRN1371 demonstrates prolonged FGFR inhibition in vivo.
Key Molecule: Fibroblast growth factor receptor 2 (FGFR2) [1]
Sensitive Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
 Disease Info 
Molecule Alteration Missense mutation
p.K660N (c.1980G>C)
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation FGF/FGFR signaling pathway Inhibition hsa01521
In Vitro Model HCT116 cells Colon Homo sapiens (Human) CVCL_0291
Hep3B cells Liver Homo sapiens (Human) CVCL_0326
RT4 cells Bladder Homo sapiens (Human) CVCL_0036
NCI-H716 cells Colon Homo sapiens (Human) CVCL_1581
RT112 cells Bladder Homo sapiens (Human) CVCL_1670
AN3CA cells Ovary Homo sapiens (Human) CVCL_0028
Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
SNU878 cells Liver Homo sapiens (Human) CVCL_5102
SNU16 cells Ascites Homo sapiens (Human) CVCL_0076
OPM2 cells Peripheral blood Homo sapiens (Human) CVCL_1625
LI7 cells Liver Homo sapiens (Human) CVCL_3840
JHH7 cells Liver Homo sapiens (Human) CVCL_2805
In Vivo Model Nude mouse PDX model Mus musculus
Experiment for
Drug Resistance		 Promega assay
Mechanism Description PRN1371 exhibits potent and durable pathway inhibition, and robust antiproliferative activity. PRN1371 demonstrates prolonged FGFR inhibition in vivo.
Key Molecule: Fibroblast growth factor receptor 3 (FGFR3) [1]
Sensitive Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
 Disease Info 
Molecule Alteration Missense mutation
p.K650M (c.1949A>T)
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation FGF/FGFR signaling pathway Inhibition hsa01521
In Vitro Model HCT116 cells Colon Homo sapiens (Human) CVCL_0291
Hep3B cells Liver Homo sapiens (Human) CVCL_0326
RT4 cells Bladder Homo sapiens (Human) CVCL_0036
NCI-H716 cells Colon Homo sapiens (Human) CVCL_1581
RT112 cells Bladder Homo sapiens (Human) CVCL_1670
AN3CA cells Ovary Homo sapiens (Human) CVCL_0028
Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
SNU878 cells Liver Homo sapiens (Human) CVCL_5102
SNU16 cells Ascites Homo sapiens (Human) CVCL_0076
OPM2 cells Peripheral blood Homo sapiens (Human) CVCL_1625
LI7 cells Liver Homo sapiens (Human) CVCL_3840
JHH7 cells Liver Homo sapiens (Human) CVCL_2805
In Vivo Model Nude mouse PDX model Mus musculus
Experiment for
Drug Resistance		 Promega assay
Mechanism Description PRN1371 exhibits potent and durable pathway inhibition, and robust antiproliferative activity. PRN1371 demonstrates prolonged FGFR inhibition in vivo.
Endometrial cancer [ICD-11: 2C76]
Click to Show/Hide
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: Fibroblast growth factor receptor 2 (FGFR2) [1]
Sensitive Disease Endometrial adenocarcinoma [ICD-11: 2C76.0]
 Disease Info 
Molecule Alteration Missense mutation
p.N549K (c.1647T>G)
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation FGF/FGFR signaling pathway Inhibition hsa01521
In Vitro Model HCT116 cells Colon Homo sapiens (Human) CVCL_0291
Hep3B cells Liver Homo sapiens (Human) CVCL_0326
RT4 cells Bladder Homo sapiens (Human) CVCL_0036
NCI-H716 cells Colon Homo sapiens (Human) CVCL_1581
RT112 cells Bladder Homo sapiens (Human) CVCL_1670
AN3CA cells Ovary Homo sapiens (Human) CVCL_0028
Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
SNU878 cells Liver Homo sapiens (Human) CVCL_5102
SNU16 cells Ascites Homo sapiens (Human) CVCL_0076
OPM2 cells Peripheral blood Homo sapiens (Human) CVCL_1625
LI7 cells Liver Homo sapiens (Human) CVCL_3840
JHH7 cells Liver Homo sapiens (Human) CVCL_2805
In Vivo Model Nude mouse PDX model Mus musculus
Experiment for
Drug Resistance		 Promega assay
Mechanism Description PRN1371 exhibits potent and durable pathway inhibition, and robust antiproliferative activity. PRN1371 demonstrates prolonged FGFR inhibition in vivo.
References
Ref 1 The Irreversible Covalent Fibroblast Growth Factor Receptor Inhibitor PRN1371 Exhibits Sustained Inhibition of FGFR after Drug ClearanceMol Cancer Ther. 2017 Dec;16(12):2668-2676. doi: 10.1158/1535-7163.MCT-17-0309. Epub 2017 Oct 4.

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