Drug Information
Drug (ID: DG01562) and It's Reported Resistant Information
| Name |
A66
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|---|---|---|---|---|---|
| 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)
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| Structure |
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| Drug Resistance Disease(s) |
Disease(s) with Resistance Information Discovered by Cell Line Test for This Drug
(1 diseases)
[1]
|
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| Target | Dopamine transporter (DAT) | SC6A3_HUMAN | [1] | ||
| Click to Show/Hide the Molecular Information and External Link(s) of This Drug | |||||
| Formula |
4
|
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| IsoSMILES |
CC1=C(SC(=N1)NC(=O)N2CCC[C@H]2C(=O)N)C3=CSC(=N3)C(C)(C)C
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| 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
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| InChIKey |
HBPXWEPKNBHKAX-NSHDSACASA-N
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| PubChem CID | |||||
Type(s) of Resistant Mechanism of This Drug
Drug Resistance Data Categorized by Their Corresponding Diseases
ICD-02: Benign/in-situ/malignant neoplasm
| Drug Resistance Data Categorized by Their Corresponding Mechanisms | ||||
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| 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) |
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| 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 | |||||||||||||
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| 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) |
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| Wild Type Structure | Method: Electron microscopy | Resolution: 2.41 Å | |||||||||||
| Mutant Type Structure | Method: X-ray diffraction | Resolution: 2.61 Å | |||||||||||
| Download The Information of Sequence | Download The Structure File | ||||||||||||
-
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 | ||||||||||||
| Drug Sensitivity Data Categorized by Their Corresponding Mechanisms | ||||
|
|
||||
| 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. | |||
| Drug Sensitivity Data Categorized by Their Corresponding Mechanisms | |||||||||||||
|
|
|||||||||||||
| 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 | |||||||||||
| Mutant Type Structure | Method: X-ray diffraction | Resolution: 2.61 Å | |||||||||||
| Download The Information of Sequence | Download The Structure File | ||||||||||||
-
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
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