Drug (ID: DG01562) and It's Reported Resistant Information
Name
A66
Synonyms
1166227-08-2; A66; A 66; (S)-N1-(2-(tert-butyl)-4'-methyl-[4,5'-bithiazol]-2'-yl)pyrrolidine-1,2-dicarboxamide; CHEMBL3218581; C17H23N5O2S2; A-66; (2S)-1-N-[5-(2-tert-butyl-1,3-thiazol-4-yl)-4-methyl-1,3-thiazol-2-yl]pyrrolidine-1,2-dicarboxamide; (2S)-N1-[2-(tert-Butyl)-4'-methyl[4,5'-bithiazol]-2'-yl]-1,2-pyrrolidinedicarboxamide; MLS006010983; SCHEMBL14833311; CHEBI:91449; AOB2329; DTXSID80655299; BCPP000449; BCP03474; EX-A1124; BDBM50042922; s2636; ZINC43206649; AKOS025293511; BA41291; BCP9000211; CCG-268577; CS-0477; A66, >=98% (HPLC); AC-33133; AS-74623; HY-13261; SMR004702785; BCP0726000206; A 66; A-66; SW218196-2; X7447; C71541; J-501023; Q27163295; (2S)-N1-(5-(2-tert-butylthiazol-4-yl)-4-methylthiazol-2-yl)pyrrolidine-1,2-dicarboxamide; (2S)-N1-[5-(2-tert-butyl-4-thiazolyl)-4-methyl-2-thiazolyl]pyrrolidine-1,2-dicarboxamide; (S)-N1-(2-tert-butyl-4'-methyl-4,5'-bithiazol-2'-yl)pyrrolidine-1,2-dicarboxamide; (2S)-N~1~-(2-tert-Butyl-4'-methyl[4,5'-bi-1,3-thiazol]-2'-yl)pyrrolidine-1,2-dicarboxamide; (2S)-N1-[2-(1,1-Dimethylethyl)-4'-methyl[4,5'-bithiazol]-2'-yl]-1,2-pyrrolidinedicarboxamide; (2S)-N1-[5-(2-TERT-BUTYL-1,3-THIAZOL-4-YL)-4-METHYL-1,3-THIAZOL-2-YL]PYRROLIDINE-1,2-DICARBOXAMIDE; 1,2-Pyrrolidinedicarboxamide, N1-[2-(1,1-dimethylethyl)-4'-methyl[4,5'-bithiazol]-2'-yl]-, (2S)-
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Indication
In total 1 Indication(s)
Obesity [ICD-11: 5B81]
Phase 2
[1]
Structure
Drug Resistance Disease(s)
Disease(s) with Resistance Information Discovered by Cell Line Test for This Drug (1 diseases)
Solid tumour/cancer [ICD-11: 2A00-2F9Z]
[1]
Target Dopamine transporter (DAT) SC6A3_HUMAN [1]
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Formula
4
IsoSMILES
CC1=C(SC(=N1)NC(=O)N2CCC[C@H]2C(=O)N)C3=CSC(=N3)C(C)(C)C
InChI
InChI=1S/C17H23N5O2S2/c1-9-12(10-8-25-14(20-10)17(2,3)4)26-15(19-9)21-16(24)22-7-5-6-11(22)13(18)23/h8,11H,5-7H2,1-4H3,(H2,18,23)(H,19,21,24)/t11-/m0/s1
InChIKey
HBPXWEPKNBHKAX-NSHDSACASA-N
PubChem CID
42636535
Type(s) of Resistant Mechanism of This Drug
  ADTT: Aberration of the Drug's Therapeutic Target
  UAPP: Unusual Activation of Pro-survival Pathway
Drug Resistance Data Categorized by Their Corresponding Diseases
ICD-02: Benign/in-situ/malignant neoplasm
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Solid tumour/cancer [ICD-11: 2A00-2F9Z]
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Drug Resistance Data Categorized by Their Corresponding Mechanisms
  Aberration of the Drug's Therapeutic Target (ADTT) Click to Show/Hide
Key Molecule: PI3-kinase alpha (PIK3CA) [1]
Resistant Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
Molecule Alteration Missense mutation
p.E545K (c.1633G>A)
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model Skin N.A.
In Vivo Model Mouse xenograft model Mus musculus
Mechanism Description The missense mutation p.E545K (c.1633G>A) in gene PIK3CA cause the resistance of A66 by aberration of the drug's therapeutic target
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Aberration of the Drug's Therapeutic Target (ADTT) Click to Show/Hide
Key Molecule: PI3-kinase alpha (PIK3CA) [1]
Sensitive Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
Molecule Alteration Missense mutation
p.H1047R (c.3140A>G)
Wild Type Structure Method: Electron microscopy Resolution: 2.41  Å
PDB: 8DCP
Mutant Type Structure Method: X-ray diffraction Resolution: 2.61  Å
PDB: 8V8V
   Download The Information of Sequence       Download The Structure File   
RMSD: 2.09
TM score: 0.95656
Amino acid change:
H1047R
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
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650
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670
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680
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690
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700
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710
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720
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730
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740
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750
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760
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770
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780
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790
|
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N
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800
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N
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810
|
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820
|
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830
|
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Y
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G
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C
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840
|
S
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C
C
V
V
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850
|
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860
|
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870
|
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880
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890
|
Y
Y
D
D
A
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900
|
S
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C
C
A
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G
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Y
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910
|
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L
L
G
G
I
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G
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D
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H
H
N
N
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920
|
N
N
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M
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D
D
D
D
G
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930
|
F
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H
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940
|
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K
K
K
K
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Y
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950
|
E
E
R
R
V
V
P
P
F
F
V
V
L
L
T
T
Q
Q
D
D
960
|
F
F
L
L
I
I
V
V
I
I
S
S
K
K
G
G
A
A
Q
Q
970
|
E
E
C
C
T
T
K
K
T
T
R
R
E
E
F
F
E
E
R
R
980
|
F
F
Q
Q
E
E
M
M
C
C
Y
Y
K
K
A
A
Y
Y
L
L
990
|
A
A
I
I
R
R
Q
Q
H
H
A
A
N
N
L
L
F
F
I
I
1000
|
N
N
L
L
F
F
S
S
M
M
M
M
L
L
G
G
S
S
G
G
1010
|
M
M
P
P
E
E
L
L
Q
Q
S
S
F
F
D
D
D
D
I
I
1020
|
A
A
Y
Y
I
I
R
R
K
K
T
T
L
L
A
A
L
L
D
D
1030
|
K
K
T
T
E
E
Q
Q
E
E
A
A
L
L
E
E
Y
Y
F
F
1040
|
M
M
K
K
Q
Q
M
M
N
N
D
D
A
A
H
R
H
H
G
G
1050
|
G
G
W
W
T
T
T
T
K
K
M
M
D
D
W
W
I
I
F
F
1060
|
H
H
T
T
I
I
K
K
Q
Q
H
H
A
A
L
L
N
N
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model Skin N.A.
In Vivo Model Mouse xenograft model Mus musculus
Mechanism Description The missense mutation p.H1047R (c.3140A>G) in gene PIK3CA cause the sensitivity of A66 by aberration of the drug's therapeutic target
Breast cancer [ICD-11: 2C60]
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: N-6 adenine-specific DNA methyltransferase 1 (N6AMT1) [2]
Sensitive Disease Breast adenocarcinoma [ICD-11: 2C60.1]
Molecule Alteration Expression
Down-regulation
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation PI3K/AKT signaling pathway Activation hsa04151
In Vitro Model MCF-7 TamR cells Breast Homo sapiens (Human) CVCL_0031
T47D TamR cells Breast Homo sapiens (Human) N.A.
Experiment for
Molecule Alteration
Western blot assay; qRT-PCR
Experiment for
Drug Resistance
CCK8 assay
Mechanism Description We discover, via bioinformatics analysis and clinical samples, that N6 adenine-specific DNA methyltransferase 1 (N6AMT1) is highly expressed in luminal breast cancer but downregulated in tamoxifen-resistant (TamR) BC cells. ChIP-qPCR and luciferase reporter assays showed that FOXA1 binds to the N6AMT1 promoter and enhances its transcription. In TamR models, FOXA1 and N6AMT1 are downregulated, increasing p110alpha protein levels (but not mRNA), phospho-AKT levels, and tamoxifen resistance. In vivo, N6AMT1 overexpression enhanced tamoxifen sensitivity, while knockdown reduced it; this sensitivity could be restored with the p110alpha inhibitor A66.
Ovarian cancer [ICD-11: 2C73]
Click to Show/Hide
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Aberration of the Drug's Therapeutic Target (ADTT) Click to Show/Hide
Key Molecule: PI3-kinase alpha (PIK3CA) [1]
Sensitive Disease Ovarian cancer [ICD-11: 2C73.0]
Molecule Alteration Missense mutation
p.H1047R (c.3140A>G)
Wild Type Structure Method: Electron microscopy Resolution: 2.41  Å
PDB: 8DCP
Mutant Type Structure Method: X-ray diffraction Resolution: 2.61  Å
PDB: 8V8V
   Download The Information of Sequence       Download The Structure File   
RMSD: 2.09
TM score: 0.95656
Amino acid change:
H1047R
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
M
-
S
-
Y
-
Y
-
H
-
H
-
H
-
-20
|
H
-
H
-
H
-
D
-
Y
-
D
-
I
-
P
-
T
-
T
-
-10
|
E
-
N
-
L
-
Y
-
F
-
Q
-
G
G
A
A
M
M
G
G
0
|
S
S
M
M
P
P
P
P
R
R
P
P
S
S
S
S
G
G
E
E
10
|
L
L
W
W
G
G
I
I
H
H
L
L
M
M
P
P
P
P
R
R
20
|
I
I
L
L
V
V
E
E
C
C
L
L
L
L
P
P
N
N
G
G
30
|
M
M
I
I
V
V
T
T
L
L
E
E
C
C
L
L
R
R
E
E
40
|
A
A
T
T
L
L
I
I
T
T
I
I
K
K
H
H
E
E
L
L
50
|
F
F
K
K
E
E
A
A
R
R
K
K
Y
Y
P
P
L
L
H
H
60
|
Q
Q
L
L
L
L
Q
Q
D
D
E
E
S
S
S
S
Y
Y
I
I
70
|
F
F
V
V
S
S
V
V
T
T
Q
Q
E
E
A
A
E
E
R
R
80
|
E
E
E
E
F
F
F
F
D
D
E
E
T
T
R
R
R
R
L
L
90
|
C
C
D
D
L
L
R
R
L
L
F
F
Q
Q
P
P
F
F
L
L
100
|
K
K
V
V
I
I
E
E
P
P
V
V
G
G
N
N
R
R
E
E
110
|
E
E
K
K
I
I
L
L
N
N
R
R
E
E
I
I
G
G
F
F
120
|
A
A
I
I
G
G
M
M
P
P
V
V
C
C
E
E
F
F
D
D
130
|
M
M
V
V
K
K
D
D
P
P
E
E
V
V
Q
Q
D
D
F
F
140
|
R
R
R
R
N
N
I
I
L
L
N
N
V
V
C
C
K
K
E
E
150
|
A
A
V
V
D
D
L
L
R
R
D
D
L
L
N
N
S
S
P
P
160
|
H
H
S
S
R
R
A
A
M
M
Y
Y
V
V
Y
Y
P
P
P
P
170
|
N
N
V
V
E
E
S
S
S
S
P
P
E
E
L
L
P
P
K
K
180
|
H
H
I
I
Y
Y
N
N
K
K
L
L
D
D
K
K
G
G
Q
Q
190
|
I
I
I
I
V
V
V
V
I
I
W
W
V
V
I
I
V
V
S
S
200
|
P
P
N
N
N
N
D
D
K
K
Q
Q
K
K
Y
Y
T
T
L
L
210
|
K
K
I
I
N
N
H
H
D
D
C
C
V
V
P
P
E
E
Q
Q
220
|
V
V
I
I
A
A
E
E
A
A
I
I
R
R
K
K
K
K
T
T
230
|
R
R
S
S
M
M
L
L
L
L
S
S
S
S
E
E
Q
Q
L
L
240
|
K
K
L
L
C
C
V
V
L
L
E
E
Y
Y
Q
Q
G
G
K
K
250
|
Y
Y
I
I
L
L
K
K
V
V
C
C
G
G
C
C
D
D
E
E
260
|
Y
Y
F
F
L
L
E
E
K
K
Y
Y
P
P
L
L
S
S
Q
Q
270
|
Y
Y
K
K
Y
Y
I
I
R
R
S
S
C
C
I
I
M
M
L
L
280
|
G
G
R
R
M
M
P
P
N
N
L
L
M
M
L
L
M
M
A
A
290
|
K
K
E
E
S
S
L
L
Y
Y
S
S
Q
Q
L
L
P
P
M
M
300
|
D
D
C
C
F
F
T
T
M
M
P
P
S
S
Y
Y
S
S
R
R
310
|
R
R
I
I
S
S
T
T
A
A
T
T
P
P
Y
Y
M
M
N
N
320
|
G
G
E
E
T
T
S
S
T
T
K
K
S
S
L
L
W
W
V
V
330
|
I
I
N
N
S
S
A
A
L
L
R
R
I
I
K
K
I
I
L
L
340
|
C
C
A
A
T
T
Y
Y
V
V
N
N
V
V
N
N
I
I
R
R
350
|
D
D
I
I
D
D
K
K
I
I
Y
Y
V
V
R
R
T
T
G
G
360
|
I
I
Y
Y
H
H
G
G
G
G
E
E
P
P
L
L
C
C
D
D
370
|
N
N
V
V
N
N
T
T
Q
Q
R
R
V
V
P
P
C
C
S
S
380
|
N
N
P
P
R
R
W
W
N
N
E
E
W
W
L
L
N
N
Y
Y
390
|
D
D
I
I
Y
Y
I
I
P
P
D
D
L
L
P
P
R
R
A
A
400
|
A
A
R
R
L
L
C
C
L
L
S
S
I
I
C
C
S
S
V
V
410
|
K
K
G
G
R
R
K
K
G
G
A
A
K
K
E
E
E
E
H
H
420
|
C
C
P
P
L
L
A
A
W
W
G
G
N
N
I
I
N
N
L
L
430
|
F
F
D
D
Y
Y
T
T
D
D
T
T
L
L
V
V
S
S
G
G
440
|
K
K
M
M
A
A
L
L
N
N
L
L
W
W
P
P
V
V
P
P
450
|
H
H
G
G
L
L
E
E
D
D
L
L
L
L
N
N
P
P
I
I
460
|
G
G
V
V
T
T
G
G
S
S
N
N
P
P
N
N
K
K
E
E
470
|
T
T
P
P
C
C
L
L
E
E
L
L
E
E
F
F
D
D
W
W
480
|
F
F
S
S
S
S
V
V
V
V
K
K
F
F
P
P
D
D
M
M
490
|
S
S
V
V
I
I
E
E
E
E
H
H
A
A
N
N
W
W
S
S
500
|
V
V
S
S
R
R
E
E
A
A
G
G
F
F
S
S
Y
Y
S
S
510
|
H
H
A
A
G
G
L
L
S
S
N
N
R
R
L
L
A
A
R
R
520
|
D
D
N
N
E
E
L
L
R
R
E
E
N
N
D
D
K
K
E
E
530
|
Q
Q
L
L
K
K
A
A
I
I
S
S
T
T
R
R
D
D
P
P
540
|
L
L
S
S
E
E
I
I
T
T
E
E
Q
Q
E
E
K
K
D
D
550
|
F
F
L
L
W
W
S
S
H
H
R
R
H
H
Y
Y
C
C
V
V
560
|
T
T
I
I
P
P
E
E
I
I
L
L
P
P
K
K
L
L
L
L
570
|
L
L
S
S
V
V
K
K
W
W
N
N
S
S
R
R
D
D
E
E
580
|
V
V
A
A
Q
Q
M
M
Y
Y
C
C
L
L
V
V
K
K
D
D
590
|
W
W
P
P
P
P
I
I
K
K
P
P
E
E
Q
Q
A
A
M
M
600
|
E
E
L
L
L
L
D
D
C
C
N
N
Y
Y
P
P
D
D
P
P
610
|
M
M
V
V
R
R
G
G
F
F
A
A
V
V
R
R
C
C
L
L
620
|
E
E
K
K
Y
Y
L
L
T
T
D
D
D
D
K
K
L
L
S
S
630
|
Q
Q
Y
Y
L
L
I
I
Q
Q
L
L
V
V
Q
Q
V
V
L
L
640
|
K
K
Y
Y
E
E
Q
Q
Y
Y
L
L
D
D
N
N
L
L
L
L
650
|
V
V
R
R
F
F
L
L
L
L
K
K
K
K
A
A
L
L
T
T
660
|
N
N
Q
Q
R
R
I
I
G
G
H
H
F
F
F
F
F
F
W
W
670
|
H
H
L
L
K
K
S
S
E
E
M
M
H
H
N
N
K
K
T
T
680
|
V
V
S
S
Q
Q
R
R
F
F
G
G
L
L
L
L
L
L
E
E
690
|
S
S
Y
Y
C
C
R
R
A
A
C
C
G
G
M
M
Y
Y
L
L
700
|
K
K
H
H
L
L
N
N
R
R
Q
Q
V
V
E
E
A
A
M
M
710
|
E
E
K
K
L
L
I
I
N
N
L
L
T
T
D
D
I
I
L
L
720
|
K
K
Q
Q
E
E
K
K
K
K
D
D
E
E
T
T
Q
Q
K
K
730
|
V
V
Q
Q
M
M
K
K
F
F
L
L
V
V
E
E
Q
Q
M
M
740
|
R
R
R
R
P
P
D
D
F
F
M
M
D
D
A
A
L
L
Q
Q
750
|
G
G
F
F
L
L
S
S
P
P
L
L
N
N
P
P
A
A
H
H
760
|
Q
Q
L
L
G
G
N
N
L
L
R
R
L
L
E
E
E
E
C
C
770
|
R
R
I
I
M
M
S
S
S
S
A
A
K
K
R
R
P
P
L
L
780
|
W
W
L
L
N
N
W
W
E
E
N
N
P
P
D
D
I
I
M
M
790
|
S
S
E
E
L
L
L
L
F
F
Q
Q
N
N
N
N
E
E
I
I
800
|
I
I
F
F
K
K
N
N
G
G
D
D
D
D
L
L
R
R
Q
Q
810
|
D
D
M
M
L
L
T
T
L
L
Q
Q
I
I
I
I
R
R
I
I
820
|
M
M
E
E
N
N
I
I
W
W
Q
Q
N
N
Q
Q
G
G
L
L
830
|
D
D
L
L
R
R
M
M
L
L
P
P
Y
Y
G
G
C
C
L
L
840
|
S
S
I
I
G
G
D
D
C
C
V
V
G
G
L
L
I
I
E
E
850
|
V
V
V
V
R
R
N
N
S
S
H
H
T
T
I
I
M
M
Q
Q
860
|
I
I
Q
Q
C
C
K
K
G
G
G
G
L
L
K
K
G
G
A
A
870
|
L
L
Q
Q
F
F
N
N
S
S
H
H
T
T
L
L
H
H
Q
Q
880
|
W
W
L
L
K
K
D
D
K
K
N
N
K
K
G
G
E
E
I
I
890
|
Y
Y
D
D
A
A
A
A
I
I
D
D
L
L
F
F
T
T
R
R
900
|
S
S
C
C
A
A
G
G
Y
Y
C
C
V
V
A
A
T
T
F
F
910
|
I
I
L
L
G
G
I
I
G
G
D
D
R
R
H
H
N
N
S
S
920
|
N
N
I
I
M
M
V
V
K
K
D
D
D
D
G
G
Q
Q
L
L
930
|
F
F
H
H
I
I
D
D
F
F
G
G
H
H
F
F
L
L
D
D
940
|
H
H
K
K
K
K
K
K
K
K
F
F
G
G
Y
Y
K
K
R
R
950
|
E
E
R
R
V
V
P
P
F
F
V
V
L
L
T
T
Q
Q
D
D
960
|
F
F
L
L
I
I
V
V
I
I
S
S
K
K
G
G
A
A
Q
Q
970
|
E
E
C
C
T
T
K
K
T
T
R
R
E
E
F
F
E
E
R
R
980
|
F
F
Q
Q
E
E
M
M
C
C
Y
Y
K
K
A
A
Y
Y
L
L
990
|
A
A
I
I
R
R
Q
Q
H
H
A
A
N
N
L
L
F
F
I
I
1000
|
N
N
L
L
F
F
S
S
M
M
M
M
L
L
G
G
S
S
G
G
1010
|
M
M
P
P
E
E
L
L
Q
Q
S
S
F
F
D
D
D
D
I
I
1020
|
A
A
Y
Y
I
I
R
R
K
K
T
T
L
L
A
A
L
L
D
D
1030
|
K
K
T
T
E
E
Q
Q
E
E
A
A
L
L
E
E
Y
Y
F
F
1040
|
M
M
K
K
Q
Q
M
M
N
N
D
D
A
A
H
R
H
H
G
G
1050
|
G
G
W
W
T
T
T
T
K
K
M
M
D
D
W
W
I
I
F
F
1060
|
H
H
T
T
I
I
K
K
Q
Q
H
H
A
A
L
L
N
N
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model Skin N.A.
In Vivo Model Mouse xenograft model Mus musculus
Mechanism Description The missense mutation p.H1047R (c.3140A>G) in gene PIK3CA cause the sensitivity of A66 by aberration of the drug's therapeutic target
References
Ref 1 A drug targeting only p110Alpha can block phosphoinositide 3-kinase signalling and tumour growth in certain cell typesBiochem J. 2011 Aug 15;438(1):53-62. doi: 10.1042/BJ20110502.
Ref 2 Reversal of endocrine resistance via N6AMT1-NEDD4L pathway-mediated p110alpha degradation. Oncogene. 2025 Mar;44(8):530-544.

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