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

  MRAP: Metabolic Reprogramming via Altered Pathways

  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]

• Resistant Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Molecule Alteration: Missense mutation; p.V211D (c.632T>A)
• 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) [3]

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

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

• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Molecule Alteration: Complex-indel; p.N486_T491delinsK (c.1458_1472del15)
• 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

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]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.L597S (c.1789_1790delCTinsTC)
• 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

Breast invasive carcinoma [ICD-11: 2C61]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Metabolic Reprogramming via Altered Pathways (MRAP)

Key Molecule: Neurofibromin 1 (NF1) [5]

• Metabolic Type: Lipid metabolism
• Sensitive Disease: ER+ breast adenocarcinoma [ICD-11: 2C61.1]
• Molecule Alteration: Mutation; .
• Experimental Note: Revealed Based on the Cell Line Data
• In Vivo Model: Rat, with ER + MCF7 cell lines; Rats
• Experiment for Molecule Alteration: LC-MS
• Experiment for Drug Resistance: Incucyte proliferation assay
• Mechanism Description: Lastly,NF1deficiency alters the synergy between metabolic inhibitors and traditional targeted inhibitors. This includes increased synergy with inhibitors targeting glycolysis, glutamine metabolism, mitochondrial fatty acid transport, and TG synthesis.

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]

• Sensitive Disease: Lymphatic system cancer [ICD-11: 2E81.1]
• Molecule Alteration: Missense mutation; p.P124L (c.371C>T)
• 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) [6]

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

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

• Sensitive Disease: Lymphatic system cancer [ICD-11: 2E81.1]
• Molecule Alteration: IF-deletion; p.P105_I107delPAI (c.314_322delCCGCAATCC)
• 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]

• Sensitive Disease: Lymphatic system cancer [ICD-11: 2E81.1]
• Molecule Alteration: Missense mutation; p.P124Q (c.371C>A)
• 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]

• Sensitive Disease: Lymphatic system cancer [ICD-11: 2E81.1]
• 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
• 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]

• Sensitive Disease: Lymphatic system cancer [ICD-11: 2E81.1]
• Molecule Alteration: Complex-indel; p.N486_T491delinsK (c.1458_1472del15)
• 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: NF1 deficiency drives metabolic reprogramming in ER+ breast cancer. Mol Metab. 2024 Feb;80:101876.
• Ref 6: 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.