Drug Information

Drug (ID: DG01527) and It's Reported Resistant Information

• Name: MRK-003
• Synonyms: MRK003; 623165-93-5; CHEMBL196215; (1'R,4R,10'S)-2-(2,2,2-Trifluoroethyl)-5'-[(E)-3-[4-(trifluoromethyl)piperidin-1-yl]prop-1-enyl]spiro[1,2,5-thiadiazolidine-4,13'-tricyclo[8.2.1.03,8]trideca-3(8),4,6-triene] 1,1-dioxide; MRK 003; MRK-003; SCHEMBL14181954; BDBM50171224; ZINC28526589; AKOS025149447; (3'R,6S,9R)-5,6,7,8,9,10-Hexahydro-5'-(2,2,2-trifluoroethyl)-2-[(1E)-3-[4-(trifluoromethyl)-1-piperidinyl]-1-propen-1-yl]spiro[6,9-methanobenzocyclooctene-11,3'-[1,2,5]thiadiazolidine] 1',1'-dioxide; (3R,6'S,9'R)-5-(2,2,2-Trifluoroethyl)-2'-((E)-3-(4-(trifluoromethyl)piperidin-1-yl)prop-1-en-1-yl)-5',6',7',8',9',10'-hexahydrospiro[[1,2,5]thiadiazolidine-3,11'-[6,9]methanobenzo[8]annulene] 1,1-dioxide; 423167-89-9; Rel-(3R,6'S,9'R)-5-(2,2,2-trifluoroethyl)-2'-((E)-3-(4-(trifluoromethyl)piperidin-1-yl)prop-1-en-1-yl)-5',6',7',8',9',10'-hexahydrospiro[[1,2,5]thiadiazolidine-3,11'-[6,9]methanobenzo[8]annulene] 1,1-dioxide
• Drug Resistance Disease(s):
  Disease(s) with Resistance Information Discovered by Cell Line Test for This Drug (1 diseases)
  Mature T-cell lymphoma [ICD-11: 2A90]; [1]
• Target: .; NOUNIPROTAC; [1]
• Formula: 4
• IsoSMILES: C1C[C@@H]2CC3=C(C[C@H]1[C@]24CN(S(=O)(=O)N4)CC(F)(F)F)C=CC(=C3)/C=C/CN5CCC(CC5)C(F)(F)F
• InChI: InChI=1S/C25H31F6N3O2S/c26-24(27,28)16-34-15-23(32-37(34,35)36)21-5-6-22(23)14-19-12-17(3-4-18(19)13-21)2-1-9-33-10-7-20(8-11-33)25(29,30)31/h1-4,12,20-22,32H,5-11,13-16H2/b2-1+/t21-,22+,23+/m0/s1
• InChIKey: NKHUILHBYOOZDF-NCOIWELASA-N
• PubChem CID: 15953832

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

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

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Neurogenic locus notch homolog protein 1 (NOTCH1) [2]

• Molecule Alteration: Missense mutation; p.A1707T (c.5119G>A)
• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: MDA-MB-157 cells; Breast; Homo sapiens (Human); CVCL_0618
• In Vitro Model: TNsBC cells; Breast; Homo sapiens (Human); N.A.
• In Vitro Model: T-ALL cells; Bone marrow; Homo sapiens (Human); CVCL_1736
• In Vitro Model: HCC2218 cells; Breast; Homo sapiens (Human); CVCL_1263
• In Vitro Model: HCC1187 cells; Breast; Homo sapiens (Human); CVCL_1247
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Cell Titer-Glo luminescent assay; Luciferase assay

Mature T-cell lymphoma [ICD-11: 2A90]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: F-box/WD repeat-containing protein 7 (FBXW7) [1]

• Molecule Alteration: Missense mutation; p.R505C (c.1513C>T)
• Resistant Disease: T-cell lymphoma [ICD-11: 2A60.3]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: T-ALL cells; Bone marrow; Homo sapiens (Human); CVCL_1736
• In Vitro Model: 293a cells; Fetal kidney; Homo sapiens (Human); CVCL_6910
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: V-FITC apoptosis detection kit I assay
• Mechanism Description: The missense mutation p.R505C (c.1513C>T) in gene FBXW7 cause the resistance of MRK-003 by unusual activation of pro-survival pathway

Key Molecule: F-box/WD repeat-containing protein 7 (FBXW7) [1]

• Molecule Alteration: Missense mutation; p.R465C (c.1393C>T)
• Resistant Disease: T-cell lymphoma [ICD-11: 2A60.3]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: T-ALL cells; Bone marrow; Homo sapiens (Human); CVCL_1736
• In Vitro Model: 293a cells; Fetal kidney; Homo sapiens (Human); CVCL_6910
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: V-FITC apoptosis detection kit I assay
• Mechanism Description: The missense mutation p.R465C (c.1393C>T) in gene FBXW7 cause the resistance of MRK-003 by unusual activation of pro-survival pathway

Key Molecule: F-box/WD repeat-containing protein 7 (FBXW7) [1]

• Molecule Alteration: Missense mutation; p.R465H (c.1394G>A)
• Resistant Disease: T-cell lymphoma [ICD-11: 2A60.3]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: T-ALL cells; Bone marrow; Homo sapiens (Human); CVCL_1736
• In Vitro Model: 293a cells; Fetal kidney; Homo sapiens (Human); CVCL_6910
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: V-FITC apoptosis detection kit I assay
• Mechanism Description: The missense mutation p.R465H (c.1394G>A) in gene FBXW7 cause the resistance of MRK-003 by unusual activation of pro-survival pathway

Key Molecule: F-box/WD repeat-containing protein 7 (FBXW7) [1]

• Molecule Alteration: Missense mutation; p.R479Q (c.1436G>A)
• Resistant Disease: T-cell lymphoma [ICD-11: 2A60.3]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: T-ALL cells; Bone marrow; Homo sapiens (Human); CVCL_1736
• In Vitro Model: 293a cells; Fetal kidney; Homo sapiens (Human); CVCL_6910
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: V-FITC apoptosis detection kit I assay
• Mechanism Description: The missense mutation p.R479Q (c.1436G>A) in gene FBXW7 cause the resistance of MRK-003 by unusual activation of pro-survival pathway

Osteosarcoma [ICD-11: 2B51]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Neurogenic locus notch homolog protein 1 (NOTCH1) [2]

• Molecule Alteration: Missense mutation; p.A1552G (c.4655C>G)
• Sensitive Disease: Osteosarcoma [ICD-11: 2B51.0]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: MDA-MB-157 cells; Breast; Homo sapiens (Human); CVCL_0618
• In Vitro Model: TNsBC cells; Breast; Homo sapiens (Human); N.A.
• In Vitro Model: T-ALL cells; Bone marrow; Homo sapiens (Human); CVCL_1736
• In Vitro Model: HCC2218 cells; Breast; Homo sapiens (Human); CVCL_1263
• In Vitro Model: HCC1187 cells; Breast; Homo sapiens (Human); CVCL_1247
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Cell Titer-Glo luminescent assay; Luciferase assay

Key Molecule: Neurogenic locus notch homolog protein 1 (NOTCH1) [2]

• Molecule Alteration: Missense mutation; p.A1552V (c.4655C>T)
• Sensitive Disease: Osteosarcoma [ICD-11: 2B51.0]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: MDA-MB-157 cells; Breast; Homo sapiens (Human); CVCL_0618
• In Vitro Model: TNsBC cells; Breast; Homo sapiens (Human); N.A.
• In Vitro Model: T-ALL cells; Bone marrow; Homo sapiens (Human); CVCL_1736
• In Vitro Model: HCC2218 cells; Breast; Homo sapiens (Human); CVCL_1263
• In Vitro Model: HCC1187 cells; Breast; Homo sapiens (Human); CVCL_1247
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Cell Titer-Glo luminescent assay; Luciferase assay

Key Molecule: Neurogenic locus notch homolog protein 1 (NOTCH1) [2]

• Molecule Alteration: Missense mutation; p.E1567K (c.4699G>A)
• Sensitive Disease: Osteosarcoma [ICD-11: 2B51.0]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: MDA-MB-157 cells; Breast; Homo sapiens (Human); CVCL_0618
• In Vitro Model: TNsBC cells; Breast; Homo sapiens (Human); N.A.
• In Vitro Model: T-ALL cells; Bone marrow; Homo sapiens (Human); CVCL_1736
• In Vitro Model: HCC2218 cells; Breast; Homo sapiens (Human); CVCL_1263
• In Vitro Model: HCC1187 cells; Breast; Homo sapiens (Human); CVCL_1247
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Cell Titer-Glo luminescent assay; Luciferase assay

Key Molecule: Neurogenic locus notch homolog protein 1 (NOTCH1) [2]

• Molecule Alteration: Missense mutation; p.A1570G (c.4709C>G)
• Sensitive Disease: Osteosarcoma [ICD-11: 2B51.0]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: MDA-MB-157 cells; Breast; Homo sapiens (Human); CVCL_0618
• In Vitro Model: TNsBC cells; Breast; Homo sapiens (Human); N.A.
• In Vitro Model: T-ALL cells; Bone marrow; Homo sapiens (Human); CVCL_1736
• In Vitro Model: HCC2218 cells; Breast; Homo sapiens (Human); CVCL_1263
• In Vitro Model: HCC1187 cells; Breast; Homo sapiens (Human); CVCL_1247
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Cell Titer-Glo luminescent assay; Luciferase assay

Key Molecule: Neurogenic locus notch homolog protein 1 (NOTCH1) [2]

• Molecule Alteration: Missense mutation; p.V1575A (c.4724T>C)
• Sensitive Disease: Osteosarcoma [ICD-11: 2B51.0]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: MDA-MB-157 cells; Breast; Homo sapiens (Human); CVCL_0618
• In Vitro Model: TNsBC cells; Breast; Homo sapiens (Human); N.A.
• In Vitro Model: T-ALL cells; Bone marrow; Homo sapiens (Human); CVCL_1736
• In Vitro Model: HCC2218 cells; Breast; Homo sapiens (Human); CVCL_1263
• In Vitro Model: HCC1187 cells; Breast; Homo sapiens (Human); CVCL_1247
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Cell Titer-Glo luminescent assay; Luciferase assay

Key Molecule: Neurogenic locus notch homolog protein 1 (NOTCH1) [2]

• Molecule Alteration: Missense mutation; p.V1599M (c.4795G>A)
• Sensitive Disease: Osteosarcoma [ICD-11: 2B51.0]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: MDA-MB-157 cells; Breast; Homo sapiens (Human); CVCL_0618
• In Vitro Model: TNsBC cells; Breast; Homo sapiens (Human); N.A.
• In Vitro Model: T-ALL cells; Bone marrow; Homo sapiens (Human); CVCL_1736
• In Vitro Model: HCC2218 cells; Breast; Homo sapiens (Human); CVCL_1263
• In Vitro Model: HCC1187 cells; Breast; Homo sapiens (Human); CVCL_1247
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Cell Titer-Glo luminescent assay; Luciferase assay

Key Molecule: Neurogenic locus notch homolog protein 1 (NOTCH1) [2]

• Molecule Alteration: Missense mutation; p.V1676I (c.5026G>A)
• Sensitive Disease: Osteosarcoma [ICD-11: 2B51.0]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: MDA-MB-157 cells; Breast; Homo sapiens (Human); CVCL_0618
• In Vitro Model: TNsBC cells; Breast; Homo sapiens (Human); N.A.
• In Vitro Model: T-ALL cells; Bone marrow; Homo sapiens (Human); CVCL_1736
• In Vitro Model: HCC2218 cells; Breast; Homo sapiens (Human); CVCL_1263
• In Vitro Model: HCC1187 cells; Breast; Homo sapiens (Human); CVCL_1247
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Cell Titer-Glo luminescent assay; Luciferase assay

Key Molecule: Neurogenic locus notch homolog protein 1 (NOTCH1) [2]

• Molecule Alteration: Missense mutation; p.I1680S (c.5039T>G)
• Sensitive Disease: Osteosarcoma [ICD-11: 2B51.0]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: MDA-MB-157 cells; Breast; Homo sapiens (Human); CVCL_0618
• In Vitro Model: TNsBC cells; Breast; Homo sapiens (Human); N.A.
• In Vitro Model: T-ALL cells; Bone marrow; Homo sapiens (Human); CVCL_1736
• In Vitro Model: HCC2218 cells; Breast; Homo sapiens (Human); CVCL_1263
• In Vitro Model: HCC1187 cells; Breast; Homo sapiens (Human); CVCL_1247
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Cell Titer-Glo luminescent assay; Luciferase assay

Key Molecule: Neurogenic locus notch homolog protein 1 (NOTCH1) [2]

• Molecule Alteration: Missense mutation; p.R1683W (c.5047C>T)
• Sensitive Disease: Osteosarcoma [ICD-11: 2B51.0]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: MDA-MB-157 cells; Breast; Homo sapiens (Human); CVCL_0618
• In Vitro Model: TNsBC cells; Breast; Homo sapiens (Human); N.A.
• In Vitro Model: T-ALL cells; Bone marrow; Homo sapiens (Human); CVCL_1736
• In Vitro Model: HCC2218 cells; Breast; Homo sapiens (Human); CVCL_1263
• In Vitro Model: HCC1187 cells; Breast; Homo sapiens (Human); CVCL_1247
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Cell Titer-Glo luminescent assay; Luciferase assay

Key Molecule: Neurogenic locus notch homolog protein 1 (NOTCH1) [2]

• Molecule Alteration: Missense mutation; p.A1707T (c.5119G>A)
• Sensitive Disease: Osteosarcoma [ICD-11: 2B51.0]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: MDA-MB-157 cells; Breast; Homo sapiens (Human); CVCL_0618
• In Vitro Model: TNsBC cells; Breast; Homo sapiens (Human); N.A.
• In Vitro Model: T-ALL cells; Bone marrow; Homo sapiens (Human); CVCL_1736
• In Vitro Model: HCC2218 cells; Breast; Homo sapiens (Human); CVCL_1263
• In Vitro Model: HCC1187 cells; Breast; Homo sapiens (Human); CVCL_1247
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Cell Titer-Glo luminescent assay; Luciferase assay

References

• Ref 1: FBW7 mutations in leukemic cells mediate NOTCH pathway activation and resistance to gamma-secretase inhibitorsJ Exp Med. 2007 Aug 6;204(8):1813-24. doi: 10.1084/jem.20070876. Epub 2007 Jul 23.
• Ref 2: Discovery of biomarkers predictive of GSI response in triple-negative breast cancer and adenoid cystic carcinomaCancer Discov. 2014 Oct;4(10):1154-67. doi: 10.1158/2159-8290.CD-13-0830. Epub 2014 Aug 7.