Drug Information

Drug (ID: DG01891) and It's Reported Resistant Information
Name
SHP099
Synonyms
SHP099
    Click to Show/Hide
Drug Resistance Disease(s)
Disease(s) with Clinically Reported Resistance for This Drug (1 diseases)
Acute myeloid leukemia [ICD-11: 2A60]
[1]
Disease(s) with Resistance Information Discovered by Cell Line Test for This Drug (1 diseases)
Colorectal cancer [ICD-11: 2B91]
[2]
Target SHP2 PTN11_HUMAN [2]
Type(s) of Resistant Mechanism of This Drug due to Structure Alteration
  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
Acute myeloid leukemia [ICD-11: 2A60]
Click to Show/Hide
Drug Resistance Data Categorized by Their Corresponding Mechanisms
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: Tyrosine-protein phosphatase non-receptor type 11 (PTPN11) [1]
Resistant Disease Acute myeloid leukemia [ICD-11: 2A60.0]
 Disease Info 
Molecule Alteration Missense mutation
p.E76K (c.226G>A)
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 1.70  Å
PDB: 5EHR
Mutant Type Structure Method: X-ray diffraction Resolution: 2.62  Å
PDB: 6CRF
   Download The Information of Sequence       Download The Structure File   
RMSD: 3.04
TM score: 0.6516
Amino acid change:
E76K
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
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0
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10
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20
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30
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40
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50
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60
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70
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80
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90
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100
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A
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110
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E
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120
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130
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140
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150
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160
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170
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E
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Y
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180
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190
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200
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210
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L
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220
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R
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A
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A
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230
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240
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250
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260
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270
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280
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290
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300
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310
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E
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320
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330
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340
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350
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360
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370
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380
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390
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400
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410
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420
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430
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440
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450
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460
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470
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480
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490
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500
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510
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520
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L
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Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
In Vitro Model TF-1 cells Bone marrow Homo sapiens (Human) CVCL_0559
Mechanism Description The SHP2 variant carrying the potent activating mutation E76K exhibits an open-state structure, which induces drastic domain reorganization to expose the active site and eliminate the binding pocket for the allosteric inhibitor SHP099.
Colorectal cancer [ICD-11: 2B91]
Click to Show/Hide
Drug Resistance Data Categorized by Their Corresponding Mechanisms
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [2]
Resistant Disease Colorectal cancer [ICD-11: 2B91.1]
 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
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420
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440
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470
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480
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490
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500
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510
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520
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530
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C
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540
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550
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560
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570
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580
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590
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V
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600
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610
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620
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630
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K
K
N
N
P
P
Y
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F
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V
V
640
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Y
Y
A
A
F
F
G
G
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L
L
Y
Y
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L
L
650
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M
M
T
T
G
G
Q
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L
L
P
P
Y
Y
S
S
N
N
I
I
660
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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
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L
S
S
P
P
D
D
L
L
S
S
680
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K
K
V
V
R
R
S
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N
N
C
C
P
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K
K
A
A
M
M
690
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K
K
R
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L
L
M
M
A
A
E
E
C
C
L
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K
700
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K
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R
R
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E
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P
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L
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710
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I
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L
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A
A
S
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E
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L
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A
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720
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Click to Show/Hide the Structure
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation RAS/ERK signaling pathway Inhibition hsa01521
In Vitro Model MDA-MB-231 cells Breast Homo sapiens (Human) CVCL_0062
NCI-H2228 cells Lung Homo sapiens (Human) CVCL_1543
MDA-MB-468 cells Breast Homo sapiens (Human) CVCL_0419
A2058 cells Skin Homo sapiens (Human) CVCL_1059
KYSE520 cells Esophagus Homo sapiens (Human) CVCL_1355
KATO-3 cells Gastric Homo sapiens (Human) CVCL_0371
Sum52 cells Pleural effusion Homo sapiens (Human) CVCL_3425
NCI-H2170 cells Lung Homo sapiens (Human) CVCL_1535
NCI-H2170 cells Lung Homo sapiens (Human) CVCL_1535
H293 cells Kidney Homo sapiens (Human) N.A.
In Vivo Model Athymic nude mouse PDX model Mus musculus
Experiment for
Drug Resistance		 CellTitre-Glo assay; Crystal violet staining assay
Mechanism Description SHP099 suppresses RAS-ERK signalling to inhibit the proliferation of receptor-tyrosine-kinase-driven human cancer cells in vitro and is efficacious in mouse tumour xenograft models.
References
Ref 1 Selective inhibition of leukemia-associated SHP2(E69K) mutant by the allosteric SHP2 inhibitor SHP099Leukemia. 2018 May;32(5):1246-1249. doi: 10.1038/s41375-018-0020-5. Epub 2018 Jan 30.
Ref 2 Allosteric inhibition of SHP2 phosphatase inhibits cancers driven by receptor tyrosine kinasesNature. 2016 Jul 7;535(7610):148-52. doi: 10.1038/nature18621. Epub 2016 Jun 29.

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