Drug Information

Drug (ID: DG01646) and It's Reported Resistant Information
Name
RAF709
Synonyms
RAF709; 1628838-42-5; RAF-709; N-[6-methyl-5-[5-morpholin-4-yl-6-(oxan-4-yloxy)pyridin-3-yl]pyridin-3-yl]-3-(trifluoromethyl)benzamide; N-{2-Methyl-5'-(Morpholin-4-Yl)-6'-[(Oxan-4-Yl)oxy][3,3'-Bipyridin]-5-Yl}-3-(Trifluoromethyl)benzamide; CHEMBL3962812; SCHEMBL16035801; BDBM202784; BCP19140; EX-A1298; s8690; AKOS030632027; CCG-269969; CS-6074; BS-15948; HY-100510; J3.655.460F; A16842; C73133; US9242969, 131; 92J; N-(2-methyl-5'-morpholino-6'-((tetrahydro-2H-pyran-4-yl)oxy)-[3,3'-bipyridin]-5-yl)-3-(trifluoromethyl)benzamide; N-(2-Methyl-5'-morpholino-6'-(tetrahydro-2H-pyran-4-yloxy)-3,3'-bipyridin-5-yl)-3-(trifluoromethyl)benzamide
    Click to Show/Hide
Structure
Click to Show/Hide the Molecular Information and External Link(s) of This Drug
Formula
6
IsoSMILES
CC1=C(C=C(C=N1)NC(=O)C2=CC(=CC=C2)C(F)(F)F)C3=CC(=C(N=C3)OC4CCOCC4)N5CCOCC5
InChI
InChI=1S/C28H29F3N4O4/c1-18-24(15-22(17-32-18)34-26(36)19-3-2-4-21(13-19)28(29,30)31)20-14-25(35-7-11-38-12-8-35)27(33-16-20)39-23-5-9-37-10-6-23/h2-4,13-17,23H,5-12H2,1H3,(H,34,36)
InChIKey
FYNMINFUAIDIFL-UHFFFAOYSA-N
PubChem CID
90408826
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
Lung cancer [ICD-11: 2C25]
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: GTPase Nras (NRAS) [1]
Sensitive Disease Lung adenocarcinoma [ICD-11: 2C25.0]
 Disease Info 
Molecule Alteration Missense mutation
p.Q61K (c.181C>A)
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 1.59  Å
PDB: 8TBI
Mutant Type Structure Method: X-ray diffraction Resolution: 1.74  Å
PDB: 8VM2
   Download The Information of Sequence       Download The Structure File   
RMSD: 0.75
TM score: 0.98025
Amino acid change:
Q61K
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
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M
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-10
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N
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Y
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0
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K
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10
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G
G
A
A
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G
G
G
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G
G
K
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A
A
L
L
20
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T
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Q
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L
L
I
I
Q
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N
N
H
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F
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30
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D
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E
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D
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40
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Y
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K
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Q
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V
V
V
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I
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D
D
G
G
E
E
50
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T
T
C
C
L
L
L
L
D
D
I
I
L
L
D
D
T
T
A
A
60
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G
G
Q
K
E
E
E
E
Y
Y
S
S
A
A
M
M
R
R
D
D
70
|
Q
Q
Y
Y
M
M
R
R
T
T
G
G
E
E
G
G
F
F
L
L
80
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C
C
V
V
F
F
A
A
I
I
N
N
N
N
S
S
K
K
S
S
90
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F
F
A
A
D
D
I
I
N
N
L
L
Y
Y
R
R
E
E
Q
Q
100
|
I
I
K
K
R
R
V
V
K
K
D
D
S
S
D
D
D
D
V
V
110
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P
P
M
M
V
V
L
L
V
V
G
G
N
N
K
K
C
C
D
D
120
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L
L
P
P
T
T
R
R
T
T
V
V
D
D
T
T
K
K
Q
Q
130
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A
A
H
H
E
E
L
L
A
A
K
K
S
S
Y
Y
G
G
I
I
140
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P
P
F
F
I
I
E
E
T
T
S
S
A
A
K
K
T
T
R
R
150
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Q
Q
G
G
V
V
E
E
D
D
A
A
F
F
Y
Y
T
T
L
L
160
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V
V
R
R
E
E
I
I
R
R
Q
Q
Y
Y
R
R
M
M
K
K
170
|
K
K
L
L
N
N
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation MAPK signaling pathway Inhibition hsa04010
In Vivo Model Nude mouse PDX model Mus musculus
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 Promega assay
Mechanism Description Targeting CRAF could sensitize response to MEK inhibitors in KRAS-mutant tumors. In addition to targeting multiple signaling nodes within the MAPK pathway to maximize both level and duration of signaling inhibition, combining RAF709 with inhibitors targeting the upstream RTK activation such as EGFR, bypass mechanisms such as YAP1 or targeting prosurvival BCL2 family members, may further enhance efficacy and reduce the development of drug resistance.
Melanoma [ICD-11: 2C30]
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: GTPase Nras (NRAS) [1]
Sensitive Disease Melanoma [ICD-11: 2C30.0]
 Disease Info 
Molecule Alteration Missense mutation
p.Q61K (c.181C>A)
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 1.59  Å
PDB: 8TBI
Mutant Type Structure Method: X-ray diffraction Resolution: 1.74  Å
PDB: 8VM2
   Download The Information of Sequence       Download The Structure File   
RMSD: 0.75
TM score: 0.98025
Amino acid change:
Q61K
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
-
M
-
H
-
H
-
H
-
H
-
H
-
H
-10
|
-
S
-
S
-
G
-
R
-
E
-
N
-
L
-
Y
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0
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M
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E
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V
V
10
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G
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A
A
G
G
G
G
V
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G
G
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K
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A
A
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L
20
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T
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I
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L
L
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N
N
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H
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30
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D
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E
E
Y
Y
D
D
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40
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Y
Y
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R
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V
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D
G
G
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E
50
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T
T
C
C
L
L
L
L
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I
L
L
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A
60
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G
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K
E
E
E
E
Y
Y
S
S
A
A
M
M
R
R
D
D
70
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Q
Q
Y
Y
M
M
R
R
T
T
G
G
E
E
G
G
F
F
L
L
80
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C
C
V
V
F
F
A
A
I
I
N
N
N
N
S
S
K
K
S
S
90
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F
F
A
A
D
D
I
I
N
N
L
L
Y
Y
R
R
E
E
Q
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100
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I
I
K
K
R
R
V
V
K
K
D
D
S
S
D
D
D
D
V
V
110
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P
P
M
M
V
V
L
L
V
V
G
G
N
N
K
K
C
C
D
D
120
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L
L
P
P
T
T
R
R
T
T
V
V
D
D
T
T
K
K
Q
Q
130
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A
A
H
H
E
E
L
L
A
A
K
K
S
S
Y
Y
G
G
I
I
140
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P
P
F
F
I
I
E
E
T
T
S
S
A
A
K
K
T
T
R
R
150
|
Q
Q
G
G
V
V
E
E
D
D
A
A
F
F
Y
Y
T
T
L
L
160
|
V
V
R
R
E
E
I
I
R
R
Q
Q
Y
Y
R
R
M
M
K
K
170
|
K
K
L
L
N
N
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation MAPK signaling pathway Inhibition hsa04010
In Vivo Model Nude mouse PDX model Mus musculus
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 Promega assay
Mechanism Description Targeting CRAF could sensitize response to MEK inhibitors in KRAS-mutant tumors. In addition to targeting multiple signaling nodes within the MAPK pathway to maximize both level and duration of signaling inhibition, combining RAF709 with inhibitors targeting the upstream RTK activation such as EGFR, bypass mechanisms such as YAP1 or targeting prosurvival BCL2 family members, may further enhance efficacy and reduce the development of drug resistance.
Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [1]
Sensitive Disease Melanoma [ICD-11: 2C30.0]
 Disease Info 
Molecule Alteration Missense mutation
p.V600E (c.1799T>A)
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 2.55  Å
PDB: 4E26
Mutant Type Structure Method: X-ray diffraction Resolution: 3.20  Å
PDB: 4G9R
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.53
TM score: 0.95765
Amino acid change:
V600E
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
420
|
M
M
D
D
R
R
G
G
S
S
H
H
H
H
H
H
H
H
H
H
430
|
H
H
G
G
S
S
E
E
D
D
R
R
N
N
R
R
M
M
K
K
440
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T
T
L
L
G
G
R
R
R
R
D
D
S
S
S
S
D
D
D
D
450
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W
W
E
E
I
I
P
P
D
D
G
G
Q
Q
I
I
T
T
V
V
460
|
G
G
Q
Q
R
R
I
I
G
G
S
S
G
G
S
S
F
F
G
G
470
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T
T
V
V
Y
Y
K
K
G
G
K
K
W
W
H
H
G
G
D
D
480
|
V
V
A
A
V
V
K
K
M
M
L
L
N
N
V
V
T
T
A
A
490
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P
P
T
T
P
P
Q
Q
Q
Q
L
L
Q
Q
A
A
F
F
K
K
500
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N
N
E
E
V
V
G
G
V
V
L
L
R
R
K
K
T
T
R
R
510
|
H
H
V
V
N
N
I
I
L
L
L
L
F
F
M
M
G
G
Y
Y
520
|
S
S
T
T
K
K
P
P
Q
Q
L
L
A
A
I
I
V
V
T
T
530
|
Q
Q
W
W
C
C
E
E
G
G
S
S
S
S
L
L
Y
Y
H
H
540
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H
H
L
L
H
H
I
I
I
I
E
E
T
T
K
K
F
F
E
E
550
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M
M
I
I
K
K
L
L
I
I
D
D
I
I
A
A
R
R
Q
Q
560
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T
T
A
A
Q
Q
G
G
M
M
D
D
Y
Y
L
L
H
H
A
A
570
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K
K
S
S
I
I
I
I
H
H
R
R
D
D
L
L
K
K
S
S
580
|
N
N
N
N
I
I
F
F
L
L
H
H
E
E
D
D
L
L
T
T
590
|
V
V
K
K
I
I
G
G
D
D
F
F
G
G
L
L
A
A
T
T
600
|
V
E
K
K
S
S
R
R
W
W
S
S
G
G
S
S
H
H
Q
Q
610
|
F
F
E
E
Q
Q
L
L
S
S
G
G
S
S
I
I
L
L
W
W
620
|
M
M
A
A
P
P
E
E
V
V
I
I
R
R
M
M
Q
Q
D
D
630
|
K
K
N
N
P
P
Y
Y
S
S
F
F
Q
Q
S
S
D
D
V
V
640
|
Y
Y
A
A
F
F
G
G
I
I
V
V
L
L
Y
Y
E
E
L
L
650
|
M
M
T
T
G
G
Q
Q
L
L
P
P
Y
Y
S
S
N
N
I
I
660
|
N
N
N
N
R
R
D
D
Q
Q
I
I
I
I
F
F
M
M
V
V
670
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G
G
R
R
G
G
Y
Y
L
L
S
S
P
P
D
D
L
L
S
S
680
|
K
K
V
V
R
R
S
S
N
N
C
C
P
P
K
K
A
A
M
M
690
|
K
K
R
R
L
L
M
M
A
A
E
E
C
C
L
L
K
K
K
K
700
|
K
K
R
R
D
D
E
E
R
R
P
P
L
L
F
F
P
P
Q
Q
710
|
I
I
L
L
A
A
S
S
I
I
E
E
L
L
L
L
A
A
R
R
720
|
S
S
L
L
P
P
K
K
I
I
H
H
R
R
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation MAPK signaling pathway Inhibition hsa04010
In Vivo Model Nude mouse PDX model Mus musculus
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 Promega assay
Mechanism Description Targeting CRAF could sensitize response to MEK inhibitors in KRAS-mutant tumors. In addition to targeting multiple signaling nodes within the MAPK pathway to maximize both level and duration of signaling inhibition, combining RAF709 with inhibitors targeting the upstream RTK activation such as EGFR, bypass mechanisms such as YAP1 or targeting prosurvival BCL2 family members, may further enhance efficacy and reduce the development of drug resistance.
Key Molecule: GTPase Nras (NRAS) [1]
Sensitive Disease Melanoma [ICD-11: 2C30.0]
 Disease Info 
Molecule Alteration Missense mutation
p.Q61L (c.182A>T)
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation MAPK signaling pathway Inhibition hsa04010
In Vivo Model Nude mouse PDX model Mus musculus
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 Promega assay
Mechanism Description Targeting CRAF could sensitize response to MEK inhibitors in KRAS-mutant tumors. In addition to targeting multiple signaling nodes within the MAPK pathway to maximize both level and duration of signaling inhibition, combining RAF709 with inhibitors targeting the upstream RTK activation such as EGFR, bypass mechanisms such as YAP1 or targeting prosurvival BCL2 family members, may further enhance efficacy and reduce the development of drug resistance.
References
Ref 1 Antitumor Properties of RAF709, a Highly Selective and Potent Inhibitor of RAF Kinase Dimers, in Tumors Driven by Mutant RAS or BRAFCancer Res. 2018 Mar 15;78(6):1537-1548. doi: 10.1158/0008-5472.CAN-17-2033. Epub 2018 Jan 17.

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