Drug Information

Drug (ID: DG01553) and It's Reported Resistant Information

• Name: Glesatinib
• Synonyms: Glesatinib; 936694-12-1; MG90265gly; UNII-7Q29OXD98N; 7Q29OXD98N; MG90265X; MG90265H9; MG90265; N-((3-fluoro-4-((2-(5-(((2-methoxyethyl)amino)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yl)oxy)phenyl)carbamothioyl)-2-(4-fluorophenyl)acetamide; N-[[3-fluoro-4-[2-[5-[(2-methoxyethylamino)methyl]pyridin-2-yl]thieno[3,2-b]pyridin-7-yl]oxyphenyl]carbamothioyl]-2-(4-fluorophenyl)acetamide; Glesatinib free base; Glesatinib [USAN]; Glesatinib (USAN/INN); SCHEMBL106319; GTPL9133; CHEMBL3989914; EX-A4139; MG-90265X; NSC791059; ZINC113139653; DB06302; NSC-791059; SB19664; compound 10a [PMID: 18434145]; NCGC00483925-01; AC-31426; HY-19642; MG-90265; CS-0016148; D11136; A857537; Q27895580; Benzeneacetamide, 4-fluoro-N-(((3-fluoro-4-((2-(5-(((2-methoxyethyl)amino)methyl)-2-pyridinyl)thieno(3,2-b)pyridin-7-yl)oxy)phenyl)amino)thioxomethyl)-; N-((3-fluoro-4-((2-(5-(((2-methoxyethyl)amino)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yl)oxy)phenyl)carbamothioyl)-2-(4-fluorophenyl)acetamid; N-(3-fluoro-4-(2-(5-((2-methoxyethylamino)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-(4-fluorophenyl)acetamide; N-(3-fluoro-4-(2-(5-((2-methoxyethylamino)methyl)pyridin-2-yl)thieno[3,2-b]pyridine-7-yloxy)phenylcarbamothioyl)-2-(4-fluorophenyl)acetamide
• Formula: 11
• IsoSMILES: COCCNCC1=CN=C(C=C1)C2=CC3=NC=CC(=C3S2)OC4=C(C=C(C=C4)NC(=S)NC(=O)CC5=CC=C(C=C5)F)F
• InChI: InChI=1S/C31H27F2N5O3S2/c1-40-13-12-34-17-20-4-8-24(36-18-20)28-16-25-30(43-28)27(10-11-35-25)41-26-9-7-22(15-23(26)33)37-31(42)38-29(39)14-19-2-5-21(32)6-3-19/h2-11,15-16,18,34H,12-14,17H2,1H3,(H2,37,38,39,42)
• InChIKey: YRCHYHRCBXNYNU-UHFFFAOYSA-N
• PubChem CID: 25181472
• DrugBank ID: DB06302

Type(s) of Resistant Mechanism of This Drug

  ADTT: Aberration of the Drug's Therapeutic Target

  EADR: Epigenetic Alteration of DNA, RNA or Protein

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Their Corresponding Diseases

ICD-02: Benign/in-situ/malignant neoplasm

Solid tumour/cancer [ICD-11: 2A00-2F9Z]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Hepatocyte growth factor receptor (MET) [1]

• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Molecule Alteration: Missense mutation; p.Y1003F (c.3008A>T)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vitro Model: WEHI-3 cells; Peripheral blood; Mus musculus (Mouse); CVCL_3622
• In Vitro Model: Hs746T cells; Skeletal muscle; Homo sapiens (Human); CVCL_0333
• In Vitro Model: Gp2-293 cells; Fetal kidney; Homo sapiens (Human); CVCL_WI48
• Experiment for Molecule Alteration: Direct sequencing assay
• Experiment for Drug Resistance: CCK-8 assay

Key Molecule: Hepatocyte growth factor receptor (MET) [1]

• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Molecule Alteration: Missense mutation; p.D1010Y (c.3028G>T)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vitro Model: WEHI-3 cells; Peripheral blood; Mus musculus (Mouse); CVCL_3622
• In Vitro Model: Hs746T cells; Skeletal muscle; Homo sapiens (Human); CVCL_0333
• In Vitro Model: Gp2-293 cells; Fetal kidney; Homo sapiens (Human); CVCL_WI48
• Experiment for Molecule Alteration: Direct sequencing assay
• Experiment for Drug Resistance: CCK-8 assay

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: Hepatocyte growth factor receptor (MET) [2]

• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Molecule Alteration: Missense mutation; p.D1228V (c.3683A>T)
• Wild Type Structure: Method: X-ray diffraction; Resolution: 1.71 Å; PDB: 5HNI
• Mutant Type Structure: Method: X-ray diffraction; Resolution: 1.67 Å; PDB: 6SDC

RMSD: 1.85; TM score: 0.88477; Amino acid change: D1228V

• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: PC9 cells; Lung; Homo sapiens (Human); CVCL_B260
• In Vitro Model: 293T cells; Breast; Homo sapiens (Human); CVCL_0063
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: There is a patient with metastatic NSCLC with MET-mediated resistance to EGFR TKI who responded to treatment with a type I MET inhibitor, savolitinib, given in combination with a third-generation EGFR inhibitor, osimertinib. The patient then developed acquired resistance mediated by a novel MET kinase domain mutation.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Hepatocyte growth factor receptor (MET) [3]

• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Molecule Alteration: Missense mutation; p.Y1230C (c.3689A>G)
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: MET signaling pathway; Inhibition; hsa04150
• In Vitro Model: NCI-H441 cells; Lung; Homo sapiens (Human); CVCL_1561
• In Vitro Model: NIH 3T3 cells; Colon; Homo sapiens (Human); CVCL_0594
• In Vitro Model: NCI-H596 cells; Lung; Homo sapiens (Human); CVCL_1571
• In Vitro Model: Hs746T cells; Skeletal muscle; Homo sapiens (Human); CVCL_0333
• In Vivo Model: Nu/Nu mouse PDX model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis

Gastric cancer [ICD-11: 2B72]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Hepatocyte growth factor receptor (MET) [4]

• Sensitive Disease: Gastric adenocarcinoma [ICD-11: 2B72.0]
• Molecule Alteration: Missense mutation; p.Y1230C (c.3689A>G)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: NCI-H441 cells; Lung; Homo sapiens (Human); CVCL_1561
• In Vitro Model: NIH 3T3 cells; Colon; Homo sapiens (Human); CVCL_0594
• In Vitro Model: SNU638 cells; Ascites; Homo sapiens (Human); CVCL_0102
• In Vitro Model: NCI-H596 cells; Lung; Homo sapiens (Human); CVCL_1571
• In Vitro Model: Hs746T cells; Skeletal muscle; Homo sapiens (Human); CVCL_0333
• In Vivo Model: Nu/nu mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis

References

• Ref 1: Sensitivity and Resistance of MET Exon 14 Mutations in Lung Cancer to Eight MET Tyrosine Kinase Inhibitors In VitroJ Thorac Oncol. 2019 Oct;14(10):1753-1765. doi: 10.1016/j.jtho.2019.06.023. Epub 2019 Jul 3.
• Ref 2: Acquired METD1228V Mutation and Resistance to MET Inhibition in Lung Cancer. Cancer Discov. 2016 Dec;6(12):1334-1341. doi: 10.1158/2159-8290.CD-16-0686. Epub 2016 Sep 30.
• Ref 3: Glesatinib Exhibits Antitumor Activity in Lung Cancer Models and Patients Harboring MET Exon 14 Mutations and Overcomes Mutation-mediated Resistance to Type I MET Inhibitors in Nonclinical ModelsClin Cancer Res. 2017 Nov 1;23(21):6661-6672. doi: 10.1158/1078-0432.CCR-17-1192. Epub 2017 Aug 1.
• Ref 4: Molecular mechanisms of heptaplatin effective against cisplatin-resistant cancer cell lines: less involvement of metallothioneinCancer Cell Int. 2004 Oct 19;4(1):6. doi: 10.1186/1475-2867-4-6.