Drug Information

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
• 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]
• 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

Colorectal cancer [ICD-11: 2B91]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [1]

• Sensitive Disease: Colorectal cancer [ICD-11: 2B91.1]
• Molecule Alteration: Missense mutation; p.G596R (c.1786G>C)
• 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
• In Vitro Model: NCI-H508 cells; Colon; Homo sapiens (Human); CVCL_1564
• In Vitro Model: HEK 293 cells; Kidney; Homo sapiens (Human); CVCL_0045
• In Vitro Model: Nras cells; N.A.; N.A.; N.A.
• In Vitro Model: NCI-H1838 cells; Lung; Homo sapiens (Human); CVCL_1499
• In Vitro Model: KRAS cells; N.A.; N.A.; N.A.
• In Vitro Model: Hras cells; N.A.; N.A.; N.A.
• In Vivo Model: Athymic Balb/C nude mouse model; Mus musculus
• Experiment for Molecule Alteration: Western blot 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]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [1]

• Resistant Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Molecule Alteration: Missense mutation; p.G469A (c.1406G>C)
• 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
• In Vitro Model: NCI-H508 cells; Colon; Homo sapiens (Human); CVCL_1564
• In Vitro Model: HEK 293 cells; Kidney; Homo sapiens (Human); CVCL_0045
• In Vitro Model: Nras cells; N.A.; N.A.; N.A.
• In Vitro Model: NCI-H1838 cells; Lung; Homo sapiens (Human); CVCL_1499
• In Vitro Model: KRAS cells; N.A.; N.A.; N.A.
• In Vitro Model: Hras cells; N.A.; N.A.; N.A.
• In Vivo Model: Athymic Balb/C nude mouse model; Mus musculus
• Experiment for Molecule Alteration: Western blot 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)

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [1]

• Sensitive Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Molecule Alteration: Missense mutation; p.G466V (c.1397G>T)
• 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
• In Vitro Model: NCI-H508 cells; Colon; Homo sapiens (Human); CVCL_1564
• In Vitro Model: HEK 293 cells; Kidney; Homo sapiens (Human); CVCL_0045
• In Vitro Model: Nras cells; N.A.; N.A.; N.A.
• In Vitro Model: NCI-H1838 cells; Lung; Homo sapiens (Human); CVCL_1499
• In Vitro Model: KRAS cells; N.A.; N.A.; N.A.
• In Vitro Model: Hras cells; N.A.; N.A.; N.A.
• In Vivo Model: Athymic Balb/C nude mouse model; Mus musculus
• Experiment for Molecule Alteration: Western blot 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]

• Sensitive Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Molecule Alteration: Missense mutation; p.N581D (c.1741A>G)
• 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
• In Vitro Model: NCI-H508 cells; Colon; Homo sapiens (Human); CVCL_1564
• In Vitro Model: HEK 293 cells; Kidney; Homo sapiens (Human); CVCL_0045
• In Vitro Model: Nras cells; N.A.; N.A.; N.A.
• In Vitro Model: NCI-H1838 cells; Lung; Homo sapiens (Human); CVCL_1499
• In Vitro Model: KRAS cells; N.A.; N.A.; N.A.
• In Vitro Model: Hras cells; N.A.; N.A.; N.A.
• In Vivo Model: Athymic Balb/C nude mouse model; Mus musculus
• Experiment for Molecule Alteration: Western blot 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]

• Sensitive Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Molecule Alteration: Missense mutation; p.D594N (c.1780G>A)
• 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
• In Vitro Model: NCI-H508 cells; Colon; Homo sapiens (Human); CVCL_1564
• In Vitro Model: HEK 293 cells; Kidney; Homo sapiens (Human); CVCL_0045
• In Vitro Model: Nras cells; N.A.; N.A.; N.A.
• In Vitro Model: NCI-H1838 cells; Lung; Homo sapiens (Human); CVCL_1499
• In Vitro Model: KRAS cells; N.A.; N.A.; N.A.
• In Vitro Model: Hras cells; N.A.; N.A.; N.A.
• In Vivo Model: Athymic Balb/C nude mouse model; Mus musculus
• Experiment for Molecule Alteration: Western blot 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]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [1]

• Resistant Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.V600E (c.1799T>A)
• Wild Type Structure: Method: X-ray diffraction; Resolution: 2.55 Å; PDB: 4E26
• Mutant Type Structure: Method: X-ray diffraction; Resolution: 3.20 Å; PDB: 4G9R

RMSD: 1.53; TM score: 0.95765; Amino acid change: V600E

• 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
• In Vitro Model: NCI-H508 cells; Colon; Homo sapiens (Human); CVCL_1564
• In Vitro Model: HEK 293 cells; Kidney; Homo sapiens (Human); CVCL_0045
• In Vitro Model: Nras cells; N.A.; N.A.; N.A.
• In Vitro Model: NCI-H1838 cells; Lung; Homo sapiens (Human); CVCL_1499
• In Vitro Model: KRAS cells; N.A.; N.A.; N.A.
• In Vitro Model: Hras cells; N.A.; N.A.; N.A.
• In Vivo Model: Athymic Balb/C nude mouse model; Mus musculus
• Experiment for Molecule Alteration: Western blot 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.