Molecule Information

General Information of the Molecule (ID: Mol00371)
Name
Fibroblast growth factor receptor 1 (FGFR1) ,Homo sapiens
Molecule Type
Protein
Gene Name
FGFR1
Gene ID
2260
Location
chr8:38400215-38468834[-]
Sequence
MWSWKCLLFWAVLVTATLCTARPSPTLPEQAQPWGAPVEVESFLVHPGDLLQLRCRLRDD
VQSINWLRDGVQLAESNRTRITGEEVEVQDSVPADSGLYACVTSSPSGSDTTYFSVNVSD
ALPSSEDDDDDDDSSSEEKETDNTKPNRMPVAPYWTSPEKMEKKLHAVPAAKTVKFKCPS
SGTPNPTLRWLKNGKEFKPDHRIGGYKVRYATWSIIMDSVVPSDKGNYTCIVENEYGSIN
HTYQLDVVERSPHRPILQAGLPANKTVALGSNVEFMCKVYSDPQPHIQWLKHIEVNGSKI
GPDNLPYVQILKTAGVNTTDKEMEVLHLRNVSFEDAGEYTCLAGNSIGLSHHSAWLTVLE
ALEERPAVMTSPLYLEIIIYCTGAFLISCMVGSVIVYKMKSGTKKSDFHSQMAVHKLAKS
IPLRRQVTVSADSSASMNSGVLLVRPSRLSSSGTPMLAGVSEYELPEDPRWELPRDRLVL
GKPLGEGCFGQVVLAEAIGLDKDKPNRVTKVAVKMLKSDATEKDLSDLISEMEMMKMIGK
HKNIINLLGACTQDGPLYVIVEYASKGNLREYLQARRPPGLEYCYNPSHNPEEQLSSKDL
VSCAYQVARGMEYLASKKCIHRDLAARNVLVTEDNVMKIADFGLARDIHHIDYYKKTTNG
RLPVKWMAPEALFDRIYTHQSDVWSFGVLLWEIFTLGGSPYPGVPVEELFKLLKEGHRMD
KPSNCTNELYMMMRDCWHAVPSQRPTFKQLVEDLDRIVALTSNQEYLDLSMPLDQYSPSF
PDTRSSTCSSGEDSVFSHEPLPEEPCLPRHPAQLANGGLKRR
    Click to Show/Hide
3D-structure
PDB ID
5A46
Classification
Transferase
Method
X-ray diffraction
Resolution
2.63  Å
Function
Tyrosine-protein kinase that acts as cell-surface receptor for fibroblast growth factors and plays an essential role in the regulation of embryonic development, cell proliferation, differentiation and migration. Required for normal mesoderm patterning and correct axial organization during embryonic development, normal skeletogenesis and normal development of the gonadotropin-releasing hormone (GnRH) neuronal system. Phosphorylates PLCG1, FRS2, GAB1 and SHB. Ligand binding leads to the activation of several signaling cascades. Activation of PLCG1 leads to the production of the cellular signaling molecules diacylglycerol and inositol 1,4,5-trisphosphate. Phosphorylation of FRS2 triggers recruitment of GRB2, GAB1, PIK3R1 and SOS1, and mediates activation of RAS, MAPK1/ERK2, MAPK3/ERK1 and the MAP kinase signaling pathway, as well as of the AKT1 signaling pathway. Promotes phosphorylation of SHC1, STAT1 and PTPN11/SHP2. In the nucleus, enhances RPS6KA1 and CREB1 activity and contributes to the regulation of transcription. FGFR1 signaling is down-regulated by IL17RD/SEF, and by FGFR1 ubiquitination, internalization and degradation.
    Click to Show/Hide
Uniprot ID
FGFR1_HUMAN
Ensembl ID
ENSG00000077782
HGNC ID
HGNC:3688
        Click to Show/Hide the Complete Species Lineage
Kingdom: Metazoa
Phylum: Chordata
Class: Mammalia
Order: Primates
Family: Hominidae
Genus: Homo
Species: Homo sapiens
Type(s) of Resistant Mechanism of This Molecule with Structure Alteration
  ADTT: Aberration of the Drug's Therapeutic Target
  UAPP: Unusual Activation of Pro-survival Pathway
Drug Resistance Data Categorized by Drug
Clinical Trial Drug(s)
2 drug(s) in total
Click to Show/Hide the Full List of Drugs
AZD-4547
Click to Show/Hide
Drug Resistance Data Categorized by Their Corresponding Mechanisms
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Disease Class: Lung adenocarcinoma [ICD-11: 2C25.0] [1]
Resistant Disease Lung adenocarcinoma [ICD-11: 2C25.0]
 Disease Info 
Resistant Drug AZD-4547
 Drug Info 
Molecule Alteration Missense mutation
p.V561M (c.1681G>A)
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 STAT3 signaling pathway Activation hsa04550
In Vitro Model L6 cells Skeletal muscle Rattus norvegicus (Rat) CVCL_0385
H1581 cells Lung Homo sapiens (Human) CVCL_1479
Experiment for
Molecule Alteration		 SDS-PAGE assay
Experiment for
Drug Resistance		 Transwell migration assay; Matrigel invasion assay; Proliferation assay; MTT assay
Mechanism Description The V561M mutation biases cells towards a more mesenchymal phenotype, including increased levels of proliferation, migration, invasion and anchorage-independent growth, which was confirmed using CyTOF, a novel single cell analysis tool. Using shRNA knockdown, loss of STAT3 restored sensitivity of cancer cells expressing V561M FGFR1 to AZD4547. Thus, the data demonstrate that combination therapies including FGFR and STAT3 may overcome V561M FGFR1 driven drug resistance in the clinic.
PRN1371
Click to Show/Hide
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Disease Class: Solid tumour/cancer [ICD-11: 2A00-2F9Z] [2]
Sensitive Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
 Disease Info 
Sensitive Drug PRN1371
 Drug Info 
Molecule Alteration Missense mutation
p.V561M (c.1681G>A)
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.
Preclinical Drug(s)
1 drug(s) in total
Click to Show/Hide the Full List of Drugs
FIIN-1
Click to Show/Hide
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Aberration of the Drug's Therapeutic Target (ADTT) Click to Show/Hide
Disease Class: Solid tumour/cancer [ICD-11: 2A00-2F9Z] [3]
Sensitive Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
 Disease Info 
Sensitive Drug FIIN-1
 Drug Info 
Molecule Alteration Missense mutation
p.V561M (c.1681G>A)
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 Revealed Based on the Cell Line Data
In Vitro Model Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
Experiment for
Drug Resistance		 CellTiter-Glo Luminescent Cell Viability Assay
Mechanism Description The missense mutation p.V561M (c.1681G>A) in gene FGFR1 cause the sensitivity of FIIN-1 by aberration of the drug's therapeutic target
References
Ref 1 The FGFR1 V561M Gatekeeper Mutation Drives AZD4547 Resistance through STAT3 Activation and EMTMol Cancer Res. 2019 Feb;17(2):532-543. doi: 10.1158/1541-7786.MCR-18-0429. Epub 2018 Sep 26.
Ref 2 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.
Ref 3 A structure-guided approach to creating covalent FGFR inhibitorsChem Biol. 2010 Mar 26;17(3):285-95. doi: 10.1016/j.chembiol.2010.02.007.

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