Drug Information

Drug (ID: DG01263) and It's Reported Resistant Information
Name
Larotrectinib
Synonyms
Larotrectinib; LOXO-101; 1223403-58-4; ARRY-470; (S)-N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide; LOXO 101; UNII-PF9462I9HX; LOXO101; PF9462I9HX; (3S)-N-[5-[(2R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]pyrazolo[1,5-a]pyrimidin-3-yl]-3-hydroxypyrrolidine-1-carboxamide; BAY2757556; BAY-2757556; Vitrakvi; ARRY 470; 1-Pyrrolidinecarboxamide, N-(5-((2R)-2-(2,5-difluorophenyl)-1-pyrrolidinyl)pyrazolo(1,5-a)pyrimidin-3-yl)-3-hydroxy-, (3S)-; 1-Pyrrolidinecarboxamide, N-[5-[(2R)-2-(2,5-difluorophenyl)-1-pyrrolidinyl]pyrazolo[1,5-a]pyrimidin-3-yl]-3-hydroxy-, (3S)-; ARRY-470; larotrectinib; Larotrectinib (USAN/INN); Larotrectinib [USAN:INN]; ARRY470; AMY264; GTPL8909; SCHEMBL2241012; CHEMBL3889654; BDBM136597; BCP16262; EX-A1981; MFCD28902192; NSC785570; NSC801004; s5860; Larotrectinib (LOXO-101 free base); example 14 [US8865698 B2]; ZINC118399834; CS-5722; DB14723; NSC-785570; NSC-801004; AC-33660; AS-35231; HY-12866; J3.628.138C; D11137; US8865698, 14; Q27081513; ARRY-470;ARRY 470 : LOXO-101; LOXO101; Larotrectinib; ARRY470;ARRY-470;ARRY 470;LOXO 101;LOXO101;Larotrectinib; (3S)-N-(5-((2R)-2-(2,5-Difluorophenyl)pyrrolidin-1-yl)pyrazolo(1,5-a)pyrimidin-3-yl)-3-hydroxypyrrolidine- 1-carboxamide; (S)-N-(5 -((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide; (S)-N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin -1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide; (S)-N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)-pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide; (S)-N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3 yl)-3-hydroxypyrrolidine-1-carboxamide
    Click to Show/Hide
Indication
In total 3 Indication(s)
Solid tumour/cancer [ICD-11: 2A00-2F9Z]
Approved
[1]
Solid tumour/cancer [ICD-11: 2A00-2F9Z]
Approved
[1]
Solid tumour/cancer [ICD-11: 2A00-2F9Z]
Approved
[1]
Structure
Drug Resistance Disease(s)
Disease(s) with Resistance Information Discovered by Cell Line Test for This Drug (1 diseases)
Brain cancer [ICD-11: 2A00]
[2]
Disease(s) with Clinically Reported Resistance for This Drug (3 diseases)
Colorectal cancer [ICD-11: 2B91]
[3]
Rhabdomyosarcoma [ICD-11: 2B55]
[1]
Solid tumour/cancer [ICD-11: 2A00-2F9Z]
[4]
Target BDNF/NT-3 growth factors receptor (TrkB) NTRK2_HUMAN [1]
NT-3 growth factor receptor (TrkC) NTRK3_HUMAN [1]
Tropomyosin-related kinase A (TrkA) NTRK1_HUMAN [1]
Click to Show/Hide the Molecular Information and External Link(s) of This Drug
Formula
C21H22F2N6O2
IsoSMILES
C1C[C@@H](N(C1)C2=NC3=C(C=NN3C=C2)NC(=O)N4CC[C@@H](C4)O)C5=C(C=CC(=C5)F)F
InChI
1S/C21H22F2N6O2/c22-13-3-4-16(23)15(10-13)18-2-1-7-28(18)19-6-9-29-20(26-19)17(11-24-29)25-21(31)27-8-5-14(30)12-27/h3-4,6,9-11,14,18,30H,1-2,5,7-8,12H2,(H,25,31)/t14-,18+/m0/s1
InChIKey
NYNZQNWKBKUAII-KBXCAEBGSA-N
PubChem CID
46188928
TTD Drug ID
D07TOK
Type(s) of Resistant Mechanism of This Drug due to Structure Alteration
  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
Click to Show/Hide the Resistance Disease of This Class
Solid tumour/cancer [ICD-11: 2A00-2F9Z]
Click to Show/Hide
Drug Resistance Data Categorized by Their Corresponding Mechanisms
  Aberration of the Drug's Therapeutic Target (ADTT) Click to Show/Hide
Key Molecule: Tropomyosin-related kinase A (TrkA) [4]
Resistant Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
 Disease Info 
Molecule Alteration Missense mutation
p.G595R (c.1783G>A)
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 2.10  Å
PDB: 5H3Q
Mutant Type Structure Method: X-ray diffraction Resolution: 2.09  Å
PDB: 8J5X
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.34
TM score: 0.93325
Amino acid change:
G595R
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
G
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S
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480
|
E
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G
-
L
-
Q
-
G
-
H
-
490
|
I
-
I
-
E
-
N
-
P
-
Q
-
Y
-
F
-
S
S
D
D
500
|
A
A
C
C
V
V
H
H
H
H
I
I
K
K
R
R
R
R
D
D
510
|
I
I
V
V
L
L
K
K
W
W
E
E
L
L
G
G
E
E
G
G
520
|
A
A
F
F
G
G
K
K
V
V
F
F
L
L
A
A
E
E
C
C
530
|
H
H
N
N
L
L
L
L
P
P
E
E
Q
Q
D
D
K
K
M
M
540
|
L
L
V
V
A
A
V
V
K
K
A
A
L
L
K
K
E
E
A
A
550
|
S
S
E
E
S
S
A
A
R
R
Q
Q
D
D
F
F
Q
Q
R
R
560
|
E
E
A
A
E
E
L
L
L
L
T
T
M
M
L
L
Q
Q
H
H
570
|
Q
Q
H
H
I
I
V
V
R
R
F
F
F
F
G
G
V
V
C
C
580
|
T
T
E
E
G
G
R
R
P
P
L
L
L
L
M
M
V
V
F
F
590
|
E
E
Y
Y
M
M
R
R
H
H
G
R
D
D
L
L
N
N
R
R
600
|
F
F
L
L
R
R
S
S
H
H
G
G
P
P
D
D
A
A
K
K
610
|
L
L
L
L
A
A
G
G
G
G
E
E
D
D
V
V
A
A
P
P
620
|
G
G
P
P
L
L
G
G
L
L
G
G
Q
Q
L
L
L
L
A
A
630
|
V
V
A
A
S
S
Q
Q
V
V
A
A
A
A
G
G
M
M
V
V
640
|
Y
Y
L
L
A
A
G
G
L
L
H
H
F
F
V
V
H
H
R
R
650
|
D
D
L
L
A
A
T
T
R
R
N
N
C
C
L
L
V
V
G
G
660
|
Q
Q
G
G
L
L
V
V
V
V
K
K
I
I
G
G
D
D
F
F
670
|
G
G
M
M
S
S
R
R
D
D
I
I
Y
Y
S
S
T
T
D
D
680
|
Y
Y
Y
Y
R
R
V
V
G
G
G
G
R
R
T
T
M
M
L
L
690
|
P
P
I
I
R
R
W
W
M
M
P
P
P
P
E
E
S
S
I
I
700
|
L
L
Y
Y
R
R
K
K
F
F
T
T
T
T
E
E
S
S
D
D
710
|
V
V
W
W
S
S
F
F
G
G
V
V
V
V
L
L
W
W
E
E
720
|
I
I
F
F
T
T
Y
Y
G
G
K
K
Q
Q
P
P
W
W
Y
Y
730
|
Q
Q
L
L
S
S
N
N
T
T
E
E
A
A
I
I
D
D
C
C
740
|
I
I
T
T
Q
Q
G
G
R
R
E
E
L
L
E
E
R
R
P
P
750
|
R
R
A
A
C
C
P
P
P
P
E
E
V
V
Y
Y
A
A
I
I
760
|
M
M
R
R
G
G
C
C
W
W
Q
Q
R
R
E
E
P
P
Q
Q
770
|
Q
Q
R
R
H
H
S
S
I
I
K
K
D
D
V
V
H
H
A
A
780
|
R
R
L
L
Q
Q
A
A
L
L
A
A
Q
Q
A
A
P
P
P
P
790
|
V
V
Y
Y
L
L
D
D
V
V
L
L
-
G
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
Rhabdomyosarcoma [ICD-11: 2B55]
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: Tropomyosin-related kinase A (TrkA) [1]
Resistant Disease Metastatic undifferentiated sarcoma [ICD-11: 2B55.Y]
 Disease Info 
Molecule Alteration Missense mutation
p.G595R
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 2.10  Å
PDB: 5H3Q
Mutant Type Structure Method: X-ray diffraction Resolution: 2.09  Å
PDB: 8J5X
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.34
TM score: 0.93325
Amino acid change:
G595R
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
G
-
S
-
S
-
L
-
S
-
P
-
T
-
480
|
E
-
G
-
K
-
G
-
S
-
G
-
L
-
Q
-
G
-
H
-
490
|
I
-
I
-
E
-
N
-
P
-
Q
-
Y
-
F
-
S
S
D
D
500
|
A
A
C
C
V
V
H
H
H
H
I
I
K
K
R
R
R
R
D
D
510
|
I
I
V
V
L
L
K
K
W
W
E
E
L
L
G
G
E
E
G
G
520
|
A
A
F
F
G
G
K
K
V
V
F
F
L
L
A
A
E
E
C
C
530
|
H
H
N
N
L
L
L
L
P
P
E
E
Q
Q
D
D
K
K
M
M
540
|
L
L
V
V
A
A
V
V
K
K
A
A
L
L
K
K
E
E
A
A
550
|
S
S
E
E
S
S
A
A
R
R
Q
Q
D
D
F
F
Q
Q
R
R
560
|
E
E
A
A
E
E
L
L
L
L
T
T
M
M
L
L
Q
Q
H
H
570
|
Q
Q
H
H
I
I
V
V
R
R
F
F
F
F
G
G
V
V
C
C
580
|
T
T
E
E
G
G
R
R
P
P
L
L
L
L
M
M
V
V
F
F
590
|
E
E
Y
Y
M
M
R
R
H
H
G
R
D
D
L
L
N
N
R
R
600
|
F
F
L
L
R
R
S
S
H
H
G
G
P
P
D
D
A
A
K
K
610
|
L
L
L
L
A
A
G
G
G
G
E
E
D
D
V
V
A
A
P
P
620
|
G
G
P
P
L
L
G
G
L
L
G
G
Q
Q
L
L
L
L
A
A
630
|
V
V
A
A
S
S
Q
Q
V
V
A
A
A
A
G
G
M
M
V
V
640
|
Y
Y
L
L
A
A
G
G
L
L
H
H
F
F
V
V
H
H
R
R
650
|
D
D
L
L
A
A
T
T
R
R
N
N
C
C
L
L
V
V
G
G
660
|
Q
Q
G
G
L
L
V
V
V
V
K
K
I
I
G
G
D
D
F
F
670
|
G
G
M
M
S
S
R
R
D
D
I
I
Y
Y
S
S
T
T
D
D
680
|
Y
Y
Y
Y
R
R
V
V
G
G
G
G
R
R
T
T
M
M
L
L
690
|
P
P
I
I
R
R
W
W
M
M
P
P
P
P
E
E
S
S
I
I
700
|
L
L
Y
Y
R
R
K
K
F
F
T
T
T
T
E
E
S
S
D
D
710
|
V
V
W
W
S
S
F
F
G
G
V
V
V
V
L
L
W
W
E
E
720
|
I
I
F
F
T
T
Y
Y
G
G
K
K
Q
Q
P
P
W
W
Y
Y
730
|
Q
Q
L
L
S
S
N
N
T
T
E
E
A
A
I
I
D
D
C
C
740
|
I
I
T
T
Q
Q
G
G
R
R
E
E
L
L
E
E
R
R
P
P
750
|
R
R
A
A
C
C
P
P
P
P
E
E
V
V
Y
Y
A
A
I
I
760
|
M
M
R
R
G
G
C
C
W
W
Q
Q
R
R
E
E
P
P
Q
Q
770
|
Q
Q
R
R
H
H
S
S
I
I
K
K
D
D
V
V
H
H
A
A
780
|
R
R
L
L
Q
Q
A
A
L
L
A
A
Q
Q
A
A
P
P
P
P
790
|
V
V
Y
Y
L
L
D
D
V
V
L
L
-
G
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
In Vitro Model NTHY-ORI-3-1 cells Thyroid gland Homo sapiens (Human) CVCL_2659
Mechanism Description After 6 months on study, restaging scans identified an isolated area of progression in the right hepatic lobe, which was resected (S3), followed by resumption of larotrectinib. NGS from S3 identified an NTRK1 G595R solvent-front mutation. Three months later, diffuse disease was noted on restaging scans.
Colorectal cancer [ICD-11: 2B91]
Click to Show/Hide
Drug Resistance Data Categorized by Their Corresponding Mechanisms
  Aberration of the Drug's Therapeutic Target (ADTT) Click to Show/Hide
Key Molecule: Tropomyosin-related kinase A (TrkA) [3]
Resistant Disease Colorectal cancer [ICD-11: 2B91.1]
 Disease Info 
Molecule Alteration Missense mutation
p.G595R (c.1783G>A)
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 2.10  Å
PDB: 5H3Q
Mutant Type Structure Method: X-ray diffraction Resolution: 2.09  Å
PDB: 8J5X
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.34
TM score: 0.93325
Amino acid change:
G595R
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
G
-
S
-
S
-
L
-
S
-
P
-
T
-
480
|
E
-
G
-
K
-
G
-
S
-
G
-
L
-
Q
-
G
-
H
-
490
|
I
-
I
-
E
-
N
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P
-
Q
-
Y
-
F
-
S
S
D
D
500
|
A
A
C
C
V
V
H
H
H
H
I
I
K
K
R
R
R
R
D
D
510
|
I
I
V
V
L
L
K
K
W
W
E
E
L
L
G
G
E
E
G
G
520
|
A
A
F
F
G
G
K
K
V
V
F
F
L
L
A
A
E
E
C
C
530
|
H
H
N
N
L
L
L
L
P
P
E
E
Q
Q
D
D
K
K
M
M
540
|
L
L
V
V
A
A
V
V
K
K
A
A
L
L
K
K
E
E
A
A
550
|
S
S
E
E
S
S
A
A
R
R
Q
Q
D
D
F
F
Q
Q
R
R
560
|
E
E
A
A
E
E
L
L
L
L
T
T
M
M
L
L
Q
Q
H
H
570
|
Q
Q
H
H
I
I
V
V
R
R
F
F
F
F
G
G
V
V
C
C
580
|
T
T
E
E
G
G
R
R
P
P
L
L
L
L
M
M
V
V
F
F
590
|
E
E
Y
Y
M
M
R
R
H
H
G
R
D
D
L
L
N
N
R
R
600
|
F
F
L
L
R
R
S
S
H
H
G
G
P
P
D
D
A
A
K
K
610
|
L
L
L
L
A
A
G
G
G
G
E
E
D
D
V
V
A
A
P
P
620
|
G
G
P
P
L
L
G
G
L
L
G
G
Q
Q
L
L
L
L
A
A
630
|
V
V
A
A
S
S
Q
Q
V
V
A
A
A
A
G
G
M
M
V
V
640
|
Y
Y
L
L
A
A
G
G
L
L
H
H
F
F
V
V
H
H
R
R
650
|
D
D
L
L
A
A
T
T
R
R
N
N
C
C
L
L
V
V
G
G
660
|
Q
Q
G
G
L
L
V
V
V
V
K
K
I
I
G
G
D
D
F
F
670
|
G
G
M
M
S
S
R
R
D
D
I
I
Y
Y
S
S
T
T
D
D
680
|
Y
Y
Y
Y
R
R
V
V
G
G
G
G
R
R
T
T
M
M
L
L
690
|
P
P
I
I
R
R
W
W
M
M
P
P
P
P
E
E
S
S
I
I
700
|
L
L
Y
Y
R
R
K
K
F
F
T
T
T
T
E
E
S
S
D
D
710
|
V
V
W
W
S
S
F
F
G
G
V
V
V
V
L
L
W
W
E
E
720
|
I
I
F
F
T
T
Y
Y
G
G
K
K
Q
Q
P
P
W
W
Y
Y
730
|
Q
Q
L
L
S
S
N
N
T
T
E
E
A
A
I
I
D
D
C
C
740
|
I
I
T
T
Q
Q
G
G
R
R
E
E
L
L
E
E
R
R
P
P
750
|
R
R
A
A
C
C
P
P
P
P
E
E
V
V
Y
Y
A
A
I
I
760
|
M
M
R
R
G
G
C
C
W
W
Q
Q
R
R
E
E
P
P
Q
Q
770
|
Q
Q
R
R
H
H
S
S
I
I
K
K
D
D
V
V
H
H
A
A
780
|
R
R
L
L
Q
Q
A
A
L
L
A
A
Q
Q
A
A
P
P
P
P
790
|
V
V
Y
Y
L
L
D
D
V
V
L
L
-
G
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
In Vitro Model Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
KM-12 cells Colon Homo sapiens (Human) CVCL_1331
In Vivo Model Balb-c nu/nu mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 Sanger sequencing assay; Western blot analysis
Experiment for
Drug Resistance		 CellTiter Glo assay; IC50 assay
References
Ref 1 Response and mechanisms of resistance to larotrectinib and selitrectinib in metastatic undifferentiated sarcoma harboring oncogenic fusion of NTRK1 .JCO Precis Oncol. 2020;4:79-90. doi: 10.1200/po.19.00287. Epub 2020 Feb 14. 10.1200/po.19.00287
Ref 2 ERK signaling promotes resistance to TRK kinase inhibition in NTRK fusion-driven glioma mouse models. Cell Rep. 2024 Oct 22;43(10):114829.
Ref 3 Mechanisms of Resistance to NTRK Inhibitors and Therapeutic Strategies in NTRK1-Rearranged CancersMol Cancer Ther. 2017 Oct;16(10):2130-2143. doi: 10.1158/1535-7163.MCT-16-0909. Epub 2017 Jul 27.
Ref 4 A Next-Generation TRK Kinase Inhibitor Overcomes Acquired Resistance to Prior TRK Kinase Inhibition in Patients with TRK Fusion-Positive Solid TumorsCancer Discov. 2017 Sep;7(9):963-972. doi: 10.1158/2159-8290.CD-17-0507. Epub 2017 Jun 3.

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