Drug Information

Drug (ID: DG01551) and It's Reported Resistant Information

• Name: Omipalisib
• Synonyms: Omipalisib; 1086062-66-9; GSK2126458; GSK-2126458; GSK 2126458; 2,4-difluoro-N-(2-methoxy-5-(4-(pyridazin-4-yl)quinolin-6-yl)pyridin-3-yl)benzenesulfonamide; 2,4-difluoro-N-[2-methoxy-5-(4-pyridazin-4-ylquinolin-6-yl)pyridin-3-yl]benzenesulfonamide; UNII-1X8F5A3NA0; 2,4-Difluoro-N-[2-methoxy-5-[4-(4-pyridazinyl)-6-quinolinyl]-3-pyridinyl]benzenesulfonamide; 1X8F5A3NA0; Omipalisib (GSK2126458, GSK458); C25H17F2N5O3S; 2,4-difluoro-N-(2-(methyloxy)-5-(4-(4-pyridazinyl)-6-quinolinyl)-3-pyridinyl)benzenesulfonamide; GSK-212; Omipalisib [USAN:INN]; GSK458; GSK 212; 2,4-difluoro-N-{2-(methyloxy)-5-[4-(4-pyridazinyl)-6-quinolinyl]-3-pyridinyl}benzenesulfonamide; Omipalisib (USAN/INN); MLS006011258; Omipalisib; GSK2126458; SCHEMBL623194; GTPL8974; Omipalisib (GSK2126458); CHEMBL1236962; CHEBI:95093; DTXSID10148604; EX-A003; GSK-458; SYN1126; 3l08; HMS3656D09; AOB87781; BCP02252; BDBM50145416; MFCD16038929; NSC764092; NSC800807; s2658; ZINC43208634; AKOS015904655; CCG-264973; CS-0085; DB12703; NSC-764092; NSC-800807; QC-7243; SB16572; NCGC00250408-01; NCGC00250408-05; AC-28458; AS-16266; Benzenesulfonamide, 2,4-difluoro-N-(2-methoxy-5-(4-(4-pyridazinyl)-6-quinolinyl)-3-pyridinyl)-; GSK2126458 (GSK458); HY-10297; SMR004703011; FT-0669061; SW219502-1; X7449; A25172; D10718; GSK-2126458;GSK 2126458; Omipalisib; J-507217; Q27088179; N-[2-Methoxy-5-[4-(4-pyridazinyl)-6-quinolinyl]-3-pyridinyl]benzenesulfonamide; ZIG
• Indication:
  In total 2 Indication(s)
  Hepatitis C virus infection [ICD-11: 1E50-1E51]; Phase 1; [1]
  Hepatitis C virus infection [ICD-11: 1E50-1E51]; Phase 1; [1]
• Target: Hepatitis C virus Non-structural 5A (HCV NS5A); POLG_HCV1; [2]
• Formula: 6
• IsoSMILES: COC1=C(C=C(C=N1)C2=CC3=C(C=CN=C3C=C2)C4=CN=NC=C4)NS(=O)(=O)C5=C(C=C(C=C5)F)F
• InChI: InChI=1S/C25H17F2N5O3S/c1-35-25-23(32-36(33,34)24-5-3-18(26)12-21(24)27)11-17(13-29-25)15-2-4-22-20(10-15)19(7-8-28-22)16-6-9-30-31-14-16/h2-14,32H,1H3
• InChIKey: CGBJSGAELGCMKE-UHFFFAOYSA-N
• PubChem CID: 25167777
• ChEBI ID: CHEBI:95093
• TTD Drug ID: D09SGV
• DrugBank ID: DB12703

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: Platelet-derived growth factor receptor alpha (PDGFRA) [1]

• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Molecule Alteration: Missense mutation; p.Y288C (c.863A>G)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: MCF10A cells; Breast; Homo sapiens (Human); CVCL_0598
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Presto blue assay
• Mechanism Description: PDGFRA Y288C induces constitutive phosphorylation of Akt, ERK1/2, and STAT3. PDGFRA Y288C is resistant to PDGFR inhibitors, such as crenolanib, but sensitive to PI3K/mTOR and MEK inhibitors, such as omipalisib and trametinib, consistent with pathway activation results.

Key Molecule: Platelet-derived growth factor receptor alpha (PDGFRA) [1]

• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Molecule Alteration: Missense mutation; p.V561D (c.1682T>A)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: MCF10A cells; Breast; Homo sapiens (Human); CVCL_0598
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Presto blue assay

Key Molecule: Platelet-derived growth factor receptor alpha (PDGFRA) [1]

• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Molecule Alteration: Missense mutation; p.D842V (c.2525A>T)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: MCF10A cells; Breast; Homo sapiens (Human); CVCL_0598
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Presto blue assay
• Mechanism Description: PDGFRA Y288C induces constitutive phosphorylation of Akt, ERK1/2, and STAT3. PDGFRA Y288C is resistant to PDGFR inhibitors, such as crenolanib, but sensitive to PI3K/mTOR and MEK inhibitors, such as omipalisib, consistent with pathway activation results.

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) [2]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• 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
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CellTiter-Glo assay
• Mechanism Description: The missense mutation p.V600E (c.1799T>A) in gene BRAF cause the sensitivity of Omipalisib by unusual activation of pro-survival pathway

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [2]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.V600K (c.1798_1799delGTinsAA)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CellTiter-Glo assay
• Mechanism Description: The missense mutation p.V600K (c.1798_1799delGTinsAA) in gene BRAF cause the sensitivity of Omipalisib by unusual activation of pro-survival pathway

References

• Ref 1: Neomorphic PDGFRA extracellular domain driver mutations are resistant to PDGFRA targeted therapiesNat Commun. 2018 Nov 2;9(1):4583. doi: 10.1038/s41467-018-06949-w.
• Ref 2: Combinations of BRAF, MEK, and PI3K/mTOR inhibitors overcome acquired resistance to the BRAF inhibitor GSK2118436 dabrafenib, mediated by NRAS or MEK mutationsMol Cancer Ther. 2012 Apr;11(4):909-20. doi: 10.1158/1535-7163.MCT-11-0989. Epub 2012 Mar 2.