Drug Information

Drug (ID: DG01309) and It's Reported Resistant Information
Name
Selpercatinib
Synonyms
Selpercatinib; 2152628-33-4; LOXO-292; CEGM9YBNGD; UNII-CEGM9YBNGD; LOXO292; 6-(2-hydroxy-2-methylpropoxy)-4-[6-[6-[(6-methoxypyridin-3-yl)methyl]-3,6-diazabicyclo[3.1.1]heptan-3-yl]pyridin-3-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile; 6-(2-hydroxy-2-methylpropoxy)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile; LY3527723; 6-(2-Hydroxy-2-methylpropoxy)-4-[6-[6-[(6-methoxy-3-pyridinyl)methyl]-3,6-diazabicyclo[3.1.1]hept-3-yl]-3-pyridinyl]pyrazolo[1,5-a]pyridine-3-carbonitrile; Serpercatinib; Retevmo; 6-(2-Hydroxy-2-methylpropoxy)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo(3.1.1)heptan-3-yl)pyridin-3-yl)pyrazolo(1,5-a)pyridine-3-carbonitrile; Retevmo (TN); Selpercatinib [INN]; Selpercatinib [USAN]; Ret inhibitor loxo-292; LOXO-292; Selpercatinib; Selpercatinib(LOXO-292); CHEMBL4559134; SCHEMBL20071478; Selpercatinib (JAN/USAN/INN); GTPL10318; BDBM296429; BCP29047; CLD62833; EX-A2859; NSC818434; s8781; WHO 10967; ZB1574; US10112942, Example 163; US10112942, Example 166; US10112942, Example 183; AKOS037649115; NSC-818434; AC-31588; BS-16622; LOXO-292;LOXO 292;LOXO292; Selpercatinib (LOXO-292, ARRY-192); example 163 [WO2018071447A1]; HY-114370; CS-0084279; LY-3527723; D11713; D77980; A929273; Pyrazolo(1,5-a)pyridine-3-carbonitrile, 6-(2-hydroxy-2-methylpropoxy)-4-(6-(6-((6-methoxy-3-pyridinyl)methyl)-3,6-diazabicyclo(3.1.1)hept-3-yl)-3-pyridinyl)-
    Click to Show/Hide
Indication
In total 3 Indication(s)
Colon cancer [ICD-11: 2B90]
Approved
[1]
Non-small-cell lung cancer [ICD-11: 2C25]
Approved
[1]
Thyroid cancer [ICD-11: 2D10]
Approved
[1]
Structure
Drug Resistance Disease(s)
Disease(s) with Clinically Reported Resistance for This Drug (2 diseases)
Lung cancer [ICD-11: 2C25]
[1]
Thyroid cancer [ICD-11: 2D10]
[1]
Disease(s) with Resistance Information Discovered by Cell Line Test for This Drug (1 diseases)
Unspecified malignant neoplasms of unspecified sites [ICD-11: 2D4Z]
[2]
Target Proto-oncogene c-Ret (RET) RET_HUMAN [1]
Click to Show/Hide the Molecular Information and External Link(s) of This Drug
Formula
C29H31N7O3
IsoSMILES
CC(C)(COC1=CN2C(=C(C=N2)C#N)C(=C1)C3=CN=C(C=C3)N4CC5CC(C4)N5CC6=CN=C(C=C6)OC)O
InChI
1S/C29H31N7O3/c1-29(2,37)18-39-24-9-25(28-21(10-30)13-33-36(28)17-24)20-5-6-26(31-12-20)34-15-22-8-23(16-34)35(22)14-19-4-7-27(38-3)32-11-19/h4-7,9,11-13,17,22-23,37H,8,14-16,18H2,1-3H3
InChIKey
XIIOFHFUYBLOLW-UHFFFAOYSA-N
PubChem CID
134436906
TTD Drug ID
D01KOA
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
Solid tumour/cancer [ICD-11: 2A00-2F9Z]
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: Proto-oncogene tyrosine-protein kinase receptor Ret (RET) [3]
Sensitive Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
 Disease Info 
Molecule Alteration Missense mutation
p.M918T (c.2753T>C)
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 1.64  Å
PDB: 7DUA
Mutant Type Structure Method: X-ray diffraction Resolution: 2.12  Å
PDB: 4CKI
   Download The Information of Sequence       Download The Structure File   
RMSD: 0.93
TM score: 0.95555
Amino acid change:
M918T
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
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700
|
G
G
P
P
L
L
S
S
L
L
S
S
V
V
D
D
A
A
F
F
710
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K
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I
I
L
L
E
E
D
D
P
P
K
K
W
W
E
E
F
F
720
|
P
P
R
R
K
K
N
N
L
L
V
V
L
L
G
G
K
K
T
T
730
|
L
L
G
G
E
E
G
G
E
E
F
F
G
G
K
K
V
V
V
V
740
|
K
K
A
A
T
T
A
A
F
F
H
H
L
L
K
K
G
G
R
R
750
|
A
A
G
G
Y
Y
T
T
T
T
V
V
A
A
V
V
K
K
M
M
760
|
L
L
K
K
E
E
N
N
A
A
S
S
P
P
S
S
E
E
L
L
770
|
R
R
D
D
L
L
L
L
S
S
E
E
F
F
N
N
V
V
L
L
780
|
K
K
Q
Q
V
V
N
N
H
H
P
P
H
H
V
V
I
I
K
K
790
|
L
L
Y
Y
G
G
A
A
C
C
S
S
Q
Q
D
D
G
G
P
P
800
|
L
L
L
L
L
L
I
I
V
V
E
E
Y
Y
A
A
K
K
Y
Y
810
|
G
G
S
S
L
L
R
R
G
G
F
F
L
L
R
R
E
E
S
S
820
|
R
R
K
K
V
V
G
G
P
P
G
G
Y
Y
L
L
G
G
S
S
830
|
G
G
G
G
S
S
R
R
N
N
S
S
S
S
S
S
L
L
D
D
840
|
H
H
P
P
D
D
E
E
R
R
A
A
L
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T
T
M
M
G
G
850
|
D
D
L
L
I
I
S
S
F
F
A
A
W
W
Q
Q
I
I
S
S
860
|
Q
Q
G
G
M
M
Q
Q
Y
Y
L
L
A
A
E
E
M
M
K
K
870
|
L
L
V
V
H
H
R
R
D
D
L
L
A
A
A
A
R
R
N
N
880
|
I
I
L
L
V
V
A
A
E
E
G
G
R
R
K
K
M
M
K
K
890
|
I
I
S
S
D
D
F
F
G
G
L
L
S
S
R
R
D
D
V
V
900
|
Y
Y
E
E
E
E
D
D
S
S
Y
Y
V
V
K
K
R
R
S
S
910
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Q
Q
G
G
R
R
I
I
P
P
V
V
K
K
W
W
M
T
A
A
920
|
I
I
E
E
S
S
L
L
F
F
D
D
H
H
I
I
Y
Y
T
T
930
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T
T
Q
Q
S
S
D
D
V
V
W
W
S
S
F
F
G
G
V
V
940
|
L
L
L
L
W
W
E
E
I
I
V
V
T
T
L
L
G
G
G
G
950
|
N
N
P
P
Y
Y
P
P
G
G
I
I
P
P
P
P
E
E
R
R
960
|
L
L
F
F
N
N
L
L
L
L
K
K
T
T
G
G
H
H
R
R
970
|
M
M
E
E
R
R
P
P
D
D
N
N
C
C
S
S
E
E
E
E
980
|
M
M
Y
Y
R
R
L
L
M
M
L
L
Q
Q
C
C
W
W
K
K
990
|
Q
Q
E
E
P
P
D
D
K
K
R
R
P
P
V
V
F
F
A
A
1000
|
D
D
I
I
S
S
K
K
D
D
L
L
E
E
K
K
M
M
M
M
1010
|
V
V
K
K
R
R
R
R
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
In Vitro Model HEK 293 cells Kidney Homo sapiens (Human) CVCL_0045
In Vivo Model Mouse PDX model Mus musculus
Mechanism Description LOXO-292 demonstrated potent and selective anti-RET activity preclinically against human cancer cell lines harboring endogenous RET gene alterations.
Thyroid cancer [ICD-11: 2D10]
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: Proto-oncogene tyrosine-protein kinase receptor Ret (RET) [3]
Sensitive Disease Thyroid gland cancer [ICD-11: 2D10.0]
 Disease Info 
Molecule Alteration Missense mutation
p.M918T (c.2753T>C)
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 1.64  Å
PDB: 7DUA
Mutant Type Structure Method: X-ray diffraction Resolution: 2.12  Å
PDB: 4CKI
   Download The Information of Sequence       Download The Structure File   
RMSD: 0.93
TM score: 0.95555
Amino acid change:
M918T
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
700
|
G
G
P
P
L
L
S
S
L
L
S
S
V
V
D
D
A
A
F
F
710
|
K
K
I
I
L
L
E
E
D
D
P
P
K
K
W
W
E
E
F
F
720
|
P
P
R
R
K
K
N
N
L
L
V
V
L
L
G
G
K
K
T
T
730
|
L
L
G
G
E
E
G
G
E
E
F
F
G
G
K
K
V
V
V
V
740
|
K
K
A
A
T
T
A
A
F
F
H
H
L
L
K
K
G
G
R
R
750
|
A
A
G
G
Y
Y
T
T
T
T
V
V
A
A
V
V
K
K
M
M
760
|
L
L
K
K
E
E
N
N
A
A
S
S
P
P
S
S
E
E
L
L
770
|
R
R
D
D
L
L
L
L
S
S
E
E
F
F
N
N
V
V
L
L
780
|
K
K
Q
Q
V
V
N
N
H
H
P
P
H
H
V
V
I
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K
K
790
|
L
L
Y
Y
G
G
A
A
C
C
S
S
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Q
D
D
G
G
P
P
800
|
L
L
L
L
L
L
I
I
V
V
E
E
Y
Y
A
A
K
K
Y
Y
810
|
G
G
S
S
L
L
R
R
G
G
F
F
L
L
R
R
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S
820
|
R
R
K
K
V
V
G
G
P
P
G
G
Y
Y
L
L
G
G
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S
830
|
G
G
G
G
S
S
R
R
N
N
S
S
S
S
S
S
L
L
D
D
840
|
H
H
P
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A
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L
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850
|
D
D
L
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W
W
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860
|
Q
Q
G
G
M
M
Q
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Y
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L
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M
M
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K
870
|
L
L
V
V
H
H
R
R
D
D
L
L
A
A
A
A
R
R
N
N
880
|
I
I
L
L
V
V
A
A
E
E
G
G
R
R
K
K
M
M
K
K
890
|
I
I
S
S
D
D
F
F
G
G
L
L
S
S
R
R
D
D
V
V
900
|
Y
Y
E
E
E
E
D
D
S
S
Y
Y
V
V
K
K
R
R
S
S
910
|
Q
Q
G
G
R
R
I
I
P
P
V
V
K
K
W
W
M
T
A
A
920
|
I
I
E
E
S
S
L
L
F
F
D
D
H
H
I
I
Y
Y
T
T
930
|
T
T
Q
Q
S
S
D
D
V
V
W
W
S
S
F
F
G
G
V
V
940
|
L
L
L
L
W
W
E
E
I
I
V
V
T
T
L
L
G
G
G
G
950
|
N
N
P
P
Y
Y
P
P
G
G
I
I
P
P
P
P
E
E
R
R
960
|
L
L
F
F
N
N
L
L
L
L
K
K
T
T
G
G
H
H
R
R
970
|
M
M
E
E
R
R
P
P
D
D
N
N
C
C
S
S
E
E
E
E
980
|
M
M
Y
Y
R
R
L
L
M
M
L
L
Q
Q
C
C
W
W
K
K
990
|
Q
Q
E
E
P
P
D
D
K
K
R
R
P
P
V
V
F
F
A
A
1000
|
D
D
I
I
S
S
K
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D
D
L
L
E
E
K
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M
M
M
M
1010
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V
V
K
K
R
R
R
R
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
In Vitro Model HEK 293 cells Kidney Homo sapiens (Human) CVCL_0045
In Vivo Model Mouse PDX model Mus musculus
Mechanism Description LOXO-292 demonstrated potent and selective anti-RET activity preclinically against human cancer cell lines harboring endogenous RET gene alterations.
References
Ref 1 Structural basis of acquired resistance to selpercatinib and pralsetinib mediated by non-gatekeeper RET mutations .Ann Oncol. 2021 Feb;32(2):261-268. doi: 10.1016/j.annonc.2020.10.599. Epub 2020 Nov 5. 10.1016/j.annonc.2020.10.599
Ref 2 YAP Regulates HER3 Signaling-Driven Adaptive Resistance to RET Inhibitors in RET-Aberrant Cancers. Clin Cancer Res. 2025 Mar 17;31(6):1127-1141.
Ref 3 Selective RET kinase inhibition for patients with RET-altered cancersAnn Oncol. 2018 Aug 1;29(8):1869-1876. doi: 10.1093/annonc/mdy137.

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