Drug Information

Drug (ID: DG01531) and It's Reported Resistant Information

• Name: Cobimetinib
• Synonyms: Cobimetinib; 934660-93-2; GDC-0973; XL518; Cotellic; Xl-518; GDC 0973; RG7420; XL 518; RG 7420; UNII-ER29L26N1X; ER29L26N1X; C21H21F3IN3O2; CHEMBL2146883; XL518 (GDC-0973); Cobimetinib (GDC-0973, RG7420); (S)-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)phenyl)(3-hydroxy-3-(piperidin-2-yl)azetidin-1-yl)methanone; [3,4-Bis(Fluoranyl)-2-[(2-Fluoranyl-4-Iodanyl-Phenyl)amino]phenyl]-[3-Oxidanyl-3-[(2s)-Piperidin-2-Yl]azetidin-1-Yl]methanone; [3,4-difluoro-2-(2-fluoro-4-iodoanilino)phenyl]-[3-hydroxy-3-[(2S)-piperidin-2-yl]azetidin-1-yl]methanone; [3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-phenyl]-((s)-3-hydroxy-3-piperidin-2-yl-azetidin-1-yl)-methanone; EUI; Cobimetinib Butyrate; Cobimetinib [USAN:INN]; cometinib; Cobimetinib (USAN/INN); SCHEMBL189565; GTPL7626; QCR-87; XL518;RG7420;Cobimetinib; CHEBI:90851; DTXSID60239435; EX-A673; GDC0973; GDC0973; XL518; Cobimetinib; 3556AH; BDBM50391802; MFCD22124461; NSC768068; NSC781257; NSC800075; s8041; ZINC60325170; BCP9000716; CCG-264727; CS-0521; DB05239; NSC-768068; NSC-781257; NSC-800075; VS-0129; NCGC00346455-03; NCGC00346455-05; (3,4-difluoro-2-(2-fluoro-4-iodophenylamino)phenyl)(3-hydroxy-3-(piperidin-2-yl)azetidin-1-yl)methanone; HY-13064; Methanone, (3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)phenyl)(3-hydroxy-3-((2S)-2-piperidinyl)-1-azetidinyl)-; RO-5514041; D10405; J-525162; Q15708292; (3,4-difluoro-2-(2-fluoro-4-iodophenylamino)phenyl)(3-hydroxy-3-((S)-piperidin-2-yl)cyclobutyl)methanone; [3,4-difluoro-2-(2-fluoro-4-iodoanilino)phenyl]-[3-hydroxy-3-[(2S)-piperidin-2-yl]azetidin; [3,4-difluoro-2-(2-fluoro-4-iodoanilino)phenyl]{3-hydroxy-3-[(2S)-piperidin-2-yl]azetidin-1-yl}methanone; [3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl]-[3-hydroxy-3-[(2S)-piperidin-2-yl]azetidin-1-yl]methanone; {3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}{3-hydroxy-3-[(2S)-piperidin-2-yl]azetidin-1-yl}methanone
• Indication:
  In total 1 Indication(s)
  Cystic fibrosis [ICD-11: CA25]; Phase 3; [1]
• Drug Resistance Disease(s):
  Disease(s) with Clinically Reported Resistance for This Drug (1 diseases)
  Solid tumour/cancer [ICD-11: 2A00-2F9Z]; [2]
• Target: cAMP-dependent chloride channel (CFTR); CFTR_HUMAN; [1]
• Formula: 4
• IsoSMILES: C1CCN[C@@H](C1)C2(CN(C2)C(=O)C3=C(C(=C(C=C3)F)F)NC4=C(C=C(C=C4)I)F)O
• InChI: InChI=1S/C21H21F3IN3O2/c22-14-6-5-13(19(18(14)24)27-16-7-4-12(25)9-15(16)23)20(29)28-10-21(30,11-28)17-3-1-2-8-26-17/h4-7,9,17,26-27,30H,1-3,8,10-11H2/t17-/m0/s1
• InChIKey: BSMCAPRUBJMWDF-KRWDZBQOSA-N
• PubChem CID: 16222096
• ChEBI ID: CHEBI:90851
• TTD Drug ID: D0W7WC
• DrugBank ID: DB05239

Type(s) of Resistant Mechanism of This Drug

  ADTT: Aberration of the Drug's Therapeutic Target

  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 Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: MAPK/ERK kinase 1 (MEK1) [2]

• Molecule Alteration: Missense mutation; p.V211D (c.632T>A)
• Resistant Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: NIH-3T3 cells; Embryo; Mus musculus (Mouse); CVCL_0594
• In Vitro Model: Phoenix AMPHO cells; Fetal kidney; Homo sapiens (Human); CVCL_H716
• In Vivo Model: NOD scid gamma xenograft model; Mus musculus
• Experiment for Molecule Alteration: Single cell sequencing assay

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]

• Molecule Alteration: Complex-indel; p.N486_T491delinsK (c.1458_1472del15)
• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• Experiment for Molecule Alteration: Whole exome sequencing; Targeted Exon Sequencing
• Experiment for Drug Resistance: CellTiter-Glo assay; IC50 assay

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [3]

• Molecule Alteration: Missense mutation; p.V600E (c.1799T>A)
• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Experimental Note: Revealed Based on the Cell Line Data
• Mechanism Description: The missense mutation p.V600E (c.1799T>A) in gene BRAF cause the sensitivity of Cobimetinib by unusual activation of pro-survival pathway

Melanoma [ICD-11: 2C30]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [4]

• Molecule Alteration: Missense mutation; p.L597S (c.1789_1790delCTinsTC)
• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: MAPK signaling pathway; Inhibition; hsa04010
• In Vitro Model: Skin sample; N.A.
• In Vivo Model: Mouse PDX model; Mus musculus
• Experiment for Drug Resistance: Crystal violet staining assay

Lymphatic system cancer [ICD-11: 2E81]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: MAPK/ERK kinase 1 (MEK1) [1]

• Molecule Alteration: Missense mutation; p.P124L (c.371C>T)
• Sensitive Disease: Lymphatic system cancer [ICD-11: 2E81.1]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• Experiment for Molecule Alteration: Whole exome sequencing; Targeted Exon Sequencing
• Experiment for Drug Resistance: CellTiter-Glo assay; IC50 assay

Key Molecule: MAPK/ERK kinase 1 (MEK1) [5]

• Molecule Alteration: Missense mutation; p.Q56P (c.167A>C)
• Sensitive Disease: Lymphatic system cancer [ICD-11: 2E81.1]
• Experimental Note: Identified from the Human Clinical Data

Key Molecule: MAPK/ERK kinase 1 (MEK1) [1]

• Molecule Alteration: IF-deletion; p.P105_I107delPAI (c.314_322delCCGCAATCC)
• Sensitive Disease: Lymphatic system cancer [ICD-11: 2E81.1]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• Experiment for Molecule Alteration: Whole exome sequencing; Targeted Exon Sequencing
• Experiment for Drug Resistance: CellTiter-Glo assay; IC50 assay

Key Molecule: MAPK/ERK kinase 1 (MEK1) [1]

• Molecule Alteration: Missense mutation; p.P124Q (c.371C>A)
• Sensitive Disease: Lymphatic system cancer [ICD-11: 2E81.1]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• Experiment for Molecule Alteration: Whole exome sequencing; Targeted Exon Sequencing
• Experiment for Drug Resistance: CellTiter-Glo assay; IC50 assay

Unusual Activation of Pro-survival Pathway (UAPP)

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

• Molecule Alteration: Complex-indel; p.N486_T491delinsK (c.1458_1472del15)
• Sensitive Disease: Lymphatic system cancer [ICD-11: 2E81.1]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• Experiment for Molecule Alteration: Whole exome sequencing; Targeted Exon Sequencing
• Experiment for Drug Resistance: CellTiter-Glo assay; IC50 assay

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

• Molecule Alteration: Missense mutation; p.V600E (c.1799T>A)
• Sensitive Disease: Lymphatic system cancer [ICD-11: 2E81.1]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• Experiment for Molecule Alteration: Whole exome sequencing; Targeted Exon Sequencing
• Experiment for Drug Resistance: CellTiter-Glo assay; IC50 assay

References

• Ref 1: Efficacy of MEK inhibition in patients with histiocytic neoplasmsNature. 2019 Mar;567(7749):521-524. doi: 10.1038/s41586-019-1012-y. Epub 2019 Mar 13.
• Ref 2: V211D Mutation in MEK1 Causes Resistance to MEK Inhibitors in Colon CancerCancer Discov. 2019 Sep;9(9):1182-1191. doi: 10.1158/2159-8290.CD-19-0356. Epub 2019 Jun 21.
• Ref 3: Mechanism of MEK inhibition determines efficacy in mutant KRAS- versus BRAF-driven cancersNature. 2013 Sep 12;501(7466):232-6. doi: 10.1038/nature12441. Epub 2013 Aug 11.
• Ref 4: Dual MAPK Inhibition Is an Effective Therapeutic Strategy for a Subset of Class II BRAF Mutant MelanomasClin Cancer Res. 2018 Dec 15;24(24):6483-6494. doi: 10.1158/1078-0432.CCR-17-3384. Epub 2018 Jun 14.
• Ref 5: Diverse and Targetable Kinase Alterations Drive Histiocytic NeoplasmsCancer Discov. 2016 Feb;6(2):154-65. doi: 10.1158/2159-8290.CD-15-0913. Epub 2015 Nov 13.