Drug (ID: DG01662) and It's Reported Resistant Information
Name
RMC-4550
Synonyms
RMC-4550; 2172651-73-7; UNII-2Q6NVG4EXB; 2Q6NVG4EXB; CHEMBL4752026; (3-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-6-(2,3-dichlorophenyl)-5-methylpyrazin-2-yl)methanol; [3-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl]-6-(2,3-dichlorophenyl)-5-methylpyrazin-2-yl]methanol; {3-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl]-6-(2,3-dichlorophenyl)-5-methylpyrazin-2-yl}methanol; 2-Pyrazinemethanol, 3-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro(4.5)dec-8-yl)-6-(2,3-dichlorophenyl)-5-methyl-; 2-Pyrazinemethanol, 3-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl]-6-(2,3-dichlorophenyl)-5-methyl-; SCHEMBL19785503; RMC-4550 (SHP2 Inhibitor); AMY16974; EX-A3075; XLD65173; BDBM50546219; MFCD31746888; s8718; ZB1559; AKOS037648879; AC-31540; BS-15923; HY-116009; CS-0063450; D70060; A929920; [3-[(3S,4S)-4-AMINO-3-METHYL-2-OXA-8-AZASPIRO[4.5]DECAN-8-YL]-6-(2,3-DICHLOROPHENYL)-5-METHYL-PYRAZIN-2-YL]METHANOL
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Structure
Drug Resistance Disease(s)
Disease(s) with Clinically Reported Resistance for This Drug (2 diseases)
Lung cancer [ICD-11: 2C25]
[1]
Melanoma [ICD-11: 2C30]
[1]
Target . NOUNIPROTAC [1]
Click to Show/Hide the Molecular Information and External Link(s) of This Drug
Formula
3
IsoSMILES
C[C@H]1[C@H](C2(CCN(CC2)C3=NC(=C(N=C3CO)C4=C(C(=CC=C4)Cl)Cl)C)CO1)N
InChI
InChI=1S/C21H26Cl2N4O2/c1-12-18(14-4-3-5-15(22)17(14)23)26-16(10-28)20(25-12)27-8-6-21(7-9-27)11-29-13(2)19(21)24/h3-5,13,19,28H,6-11,24H2,1-2H3/t13-,19+/m0/s1
InChIKey
IKUYEYLZXGGCRD-ORAYPTAESA-N
PubChem CID
134183206
Type(s) of Resistant Mechanism of This Drug
  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
Colorectal cancer [ICD-11: 2B91]
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Drug Sensitivity 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) [1]
Molecule Alteration Missense mutation
p.G596R (c.1786G>C)
Sensitive Disease Colorectal cancer [ICD-11: 2B91.1]
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation RAS/RAF/MEK/ERK signaling pathway Activation hsa01521
In Vitro Model NCI-H358 cells Lung Homo sapiens (Human) CVCL_1559
NCI-H508 cells Colon Homo sapiens (Human) CVCL_1564
HEK 293 cells Kidney Homo sapiens (Human) CVCL_0045
Nras cells N.A. . N.A.
NCI-H1838 cells Lung Homo sapiens (Human) CVCL_1499
KRAS cells N.A. . N.A.
Hras cells N.A. . N.A.
In Vivo Model Athymic Balb/C nude mouse model Mus musculus
Experiment for
Molecule Alteration
Western blotting analysis
Experiment for
Drug Resistance
Promega assay
Mechanism Description SHP2 inhibitor treatment decreases oncogenic RAS-RAF-MEK-ERK signaling and cancer growth by disrupting SOS1-mediated RAS-GTP loading.
Lung cancer [ICD-11: 2C25]
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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) [1]
Molecule Alteration Missense mutation
p.G469A (c.1406G>C)
Resistant Disease Lung adenocarcinoma [ICD-11: 2C25.0]
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation RAS/RAF/MEK/ERK signaling pathway Activation hsa01521
In Vitro Model NCI-H358 cells Lung Homo sapiens (Human) CVCL_1559
NCI-H508 cells Colon Homo sapiens (Human) CVCL_1564
HEK 293 cells Kidney Homo sapiens (Human) CVCL_0045
Nras cells N.A. . N.A.
NCI-H1838 cells Lung Homo sapiens (Human) CVCL_1499
KRAS cells N.A. . N.A.
Hras cells N.A. . N.A.
In Vivo Model Athymic Balb/C nude mouse model Mus musculus
Experiment for
Molecule Alteration
Western blotting analysis
Experiment for
Drug Resistance
Promega assay
Mechanism Description SHP2 inhibitor treatment decreases oncogenic RAS-RAF-MEK-ERK signaling and cancer growth by disrupting SOS1-mediated RAS-GTP loading.
Drug Sensitivity 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) [1]
Molecule Alteration Missense mutation
p.G466V (c.1397G>T)
Sensitive Disease Lung adenocarcinoma [ICD-11: 2C25.0]
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation RAS/RAF/MEK/ERK signaling pathway Activation hsa01521
In Vitro Model NCI-H358 cells Lung Homo sapiens (Human) CVCL_1559
NCI-H508 cells Colon Homo sapiens (Human) CVCL_1564
HEK 293 cells Kidney Homo sapiens (Human) CVCL_0045
Nras cells N.A. . N.A.
NCI-H1838 cells Lung Homo sapiens (Human) CVCL_1499
KRAS cells N.A. . N.A.
Hras cells N.A. . N.A.
In Vivo Model Athymic Balb/C nude mouse model Mus musculus
Experiment for
Molecule Alteration
Western blotting analysis
Experiment for
Drug Resistance
Promega assay
Mechanism Description SHP2 inhibitor treatment decreases oncogenic RAS-RAF-MEK-ERK signaling and cancer growth by disrupting SOS1-mediated RAS-GTP loading.
Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [1]
Molecule Alteration Missense mutation
p.N581D (c.1741A>G)
Sensitive Disease Lung adenocarcinoma [ICD-11: 2C25.0]
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation RAS/RAF/MEK/ERK signaling pathway Activation hsa01521
In Vitro Model NCI-H358 cells Lung Homo sapiens (Human) CVCL_1559
NCI-H508 cells Colon Homo sapiens (Human) CVCL_1564
HEK 293 cells Kidney Homo sapiens (Human) CVCL_0045
Nras cells N.A. . N.A.
NCI-H1838 cells Lung Homo sapiens (Human) CVCL_1499
KRAS cells N.A. . N.A.
Hras cells N.A. . N.A.
In Vivo Model Athymic Balb/C nude mouse model Mus musculus
Experiment for
Molecule Alteration
Western blotting analysis
Experiment for
Drug Resistance
Promega assay
Mechanism Description SHP2 inhibitor treatment decreases oncogenic RAS-RAF-MEK-ERK signaling and cancer growth by disrupting SOS1-mediated RAS-GTP loading.
Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [1]
Molecule Alteration Missense mutation
p.D594N (c.1780G>A)
Sensitive Disease Lung adenocarcinoma [ICD-11: 2C25.0]
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation RAS/RAF/MEK/ERK signaling pathway Activation hsa01521
In Vitro Model NCI-H358 cells Lung Homo sapiens (Human) CVCL_1559
NCI-H508 cells Colon Homo sapiens (Human) CVCL_1564
HEK 293 cells Kidney Homo sapiens (Human) CVCL_0045
Nras cells N.A. . N.A.
NCI-H1838 cells Lung Homo sapiens (Human) CVCL_1499
KRAS cells N.A. . N.A.
Hras cells N.A. . N.A.
In Vivo Model Athymic Balb/C nude mouse model Mus musculus
Experiment for
Molecule Alteration
Western blotting analysis
Experiment for
Drug Resistance
Promega assay
Mechanism Description SHP2 inhibitor treatment decreases oncogenic RAS-RAF-MEK-ERK signaling and cancer growth by disrupting SOS1-mediated RAS-GTP loading.
Melanoma [ICD-11: 2C30]
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) [1]
Molecule Alteration Missense mutation
p.V600E (c.1799T>A)
Resistant Disease Melanoma [ICD-11: 2C30.0]
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation RAS/RAF/MEK/ERK signaling pathway Activation hsa01521
In Vitro Model NCI-H358 cells Lung Homo sapiens (Human) CVCL_1559
NCI-H508 cells Colon Homo sapiens (Human) CVCL_1564
HEK 293 cells Kidney Homo sapiens (Human) CVCL_0045
Nras cells N.A. . N.A.
NCI-H1838 cells Lung Homo sapiens (Human) CVCL_1499
KRAS cells N.A. . N.A.
Hras cells N.A. . N.A.
In Vivo Model Athymic Balb/C nude mouse model Mus musculus
Experiment for
Molecule Alteration
Western blotting analysis
Experiment for
Drug Resistance
Promega assay
Mechanism Description SHP2 inhibitor treatment decreases oncogenic RAS-RAF-MEK-ERK signaling and cancer growth by disrupting SOS1-mediated RAS-GTP loading.
References
Ref 1 RAS nucleotide cycling underlies the SHP2 phosphatase dependence of mutant BRAF-, NF1- and RAS-driven cancersNat Cell Biol. 2018 Sep;20(9):1064-1073. doi: 10.1038/s41556-018-0169-1. Epub 2018 Aug 13.

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