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
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Indication
In total 1 Indication(s)
Cystic fibrosis [ICD-11: CA25]
Phase 3
[1]
Structure
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]
Click to Show/Hide the Molecular Information and External Link(s) of This Drug
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
Click to Show/Hide the Resistance Disease of This Class
Solid tumour/cancer [ICD-11: 2A00-2F9Z]
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Drug Resistance Data Categorized by Their Corresponding Mechanisms
       Aberration of the Drug's Therapeutic Target (ADTT) Click to Show/Hide
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
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) Click to Show/Hide
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]
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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) [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]
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Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
       Aberration of the Drug's Therapeutic Target (ADTT) Click to Show/Hide
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) Click to Show/Hide
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.

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