Drug Information

Drug (ID: DG01671) and It's Reported Resistant Information

• Name: BI-847325
• Synonyms: BI-847325; 1207293-36-4; BI 847325; QXD8ZW7UVZ; UNII-QXD8ZW7UVZ; (Z)-3-(3-(((4-((dimethylamino)methyl)phenyl)amino)(phenyl)methylene)-2-oxoindolin-6-yl)-N-ethylpropiolamide; BI847325; 3-(3-(((4-((Dimethylamino)methyl)phenyl)amino)(phenyl)methylene)-2-oxoindolin-6-yl)-N-ethylpropiolamide; 3-[(3~{z})-3-[[[4-[(Dimethylamino)methyl]phenyl]amino]-Phenyl-Methylidene]-2-Oxidanylidene-1~{h}-Indol-6-Yl]-~{n}-Ethyl-Prop-2-Ynamide; (Z)-3-(3-((4-((dimethylamino)methyl)phenylamino)(phenyl)methylene)-2-oxoindolin-6-yl)-N-ethylpropiolamide; 2128698-24-6; 3-(3-(((4-((Dimethylamino)methyl)phenyl)amino)phenylmethylene)-2,3-dihydro-2-oxo-1H-indol-6-yl)-N-ethyl-2-propynamide; 3-[3-[[[4-[(Dimethylamino)methyl]phenyl]amino]phenylmethylene]-2,3-dihydro-2-oxo-1H-indol-6-yl]-N-ethyl-2-propynamide; 5U5; SCHEMBL4081822; CHEMBL3699142; CHEMBL4303500; SCHEMBL10326049; BDBM142744; BCP15994; EX-A1727; NSC799360; s7843; AKOS030238788; ZINC143989489; ZINC143989696; CCG-269395; CS-6291; NSC-799360; SB23246; NCGC00481575-01; AC-29870; AS-56076; HY-18955; US8937095, 6; Q27456034; 2-Propynamide, 3-((3Z)-3-(((4-((dimethylamino)methyl)phenyl)amino)phenylmethylene)-2,3-dihydro-2-oxo-1H-indol-6-yl)-N-ethyl-; 2-Propynamide, 3-(3-(((4-((dimethylamino)methyl)phenyl)amino)phenylmethylene)-2,3-dihydro-2-oxo-1H-indol-6-yl)-N-ethyl-; 3-((3Z)-3-((4-(Dimethylaminomethyl)anilino)-phenyl-methylene)-2-oxo-indolin-6-yl)-N-ethyl-prop-2-ynamide; 3-[(3Z)-3-[({4-[(dimethylamino)methyl]phenyl}amino)(phenyl)methylidene]-2-oxo-2,3-dihydro-1H-indol-6-yl]-N-ethylprop-2-ynamide; 3-[3-[N-[4-[(dimethylamino)methyl]phenyl]-C-phenylcarbonimidoyl]-2-hydroxy-1H-indol-6-yl]-N-ethylprop-2-ynamide
• Indication:
  In total 3 Indication(s)
  Follicular lymphoma [ICD-11: 2A80]; Phase 1; [1]
  Non-hodgkin lymphoma [ICD-11: 2B33]; Phase 1; [1]
  Non-hodgkin lymphoma [ICD-11: 2B33]; Phase 1; [1]
• Target: PI3-kinase alpha (PIK3CA); PK3CA_HUMAN; [1]
• Target: PI3-kinase delta (PIK3CD); PK3CD_HUMAN; [1]
• Target: PI3-kinase gamma (PIK3CG); PK3CG_HUMAN; [1]
• Formula: 7
• IsoSMILES: CCNC(=O)C#CC1=CC2=C(C=C1)C(=C(N2)O)C(=NC3=CC=C(C=C3)CN(C)C)C4=CC=CC=C4
• InChI: InChI=1S/C29H28N4O2/c1-4-30-26(34)17-13-20-12-16-24-25(18-20)32-29(35)27(24)28(22-8-6-5-7-9-22)31-23-14-10-21(11-15-23)19-33(2)3/h5-12,14-16,18,32,35H,4,19H2,1-3H3,(H,30,34)
• InChIKey: OCUQMWSIGPQEMX-UHFFFAOYSA-N
• PubChem CID: 135567102
• TTD Drug ID: D0S5LD

Type(s) of Resistant Mechanism of This Drug

  IDUE: Irregularity in Drug Uptake and Drug Efflux

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Their Corresponding Diseases

ICD-02: Benign/in-situ/malignant neoplasm

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) [1]

• 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
• In Vitro Model: WM793 cells; N.A.; Homo sapiens (Human); CVCL_8787/CVCL_5414
• In Vitro Model: WM39 cells; Skin; Homo sapiens (Human); CVCL_2240
• In Vitro Model: WM164 cells; Skin; Homo sapiens (Human); CVCL_7928
• In Vitro Model: RPMI-7951 cells; Lymph node; Homo sapiens (Human); CVCL_1666
• In Vitro Model: 1205Lu cells; Skin; Homo sapiens (Human); CVCL_5239
• In Vivo Model: BALB SCID mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis; qPCR; Proteasome-Glo Chymotrypsin-like cell-based assay
• Experiment for Drug Resistance: Alamar blue assay; Colony formation assay

Thyroid cancer [ICD-11: 2D10]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Multidrug resistance-associated protein 1 (MRP1) [2]

• Sensitive Disease: Thyroid gland cancer [ICD-11: 2D10.0]
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: SW1736 cells; Thyroid; Homo sapiens (Human); CVCL_3883
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Apoptosis assay
• Mechanism Description: Suppression of MAPK signaling pathway activity by BI-847325 treatment could significantly decrease the expression of?MDR1?and?MRP1?genes in C643 and SW1736 ATC cell lines. BI-847325 decreased multidrug resistance through downregulation of MDR1 and MRP1.

Key Molecule: Multidrug resistance protein 1 (ABCB1) [2]

• Sensitive Disease: Thyroid gland cancer [ICD-11: 2D10.0]
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: C643 cells; Thyroid gland; Homo sapiens (Human); CVCL_5969
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Apoptosis assay
• Mechanism Description: Suppression of MAPK signaling pathway activity by BI-847325 treatment could significantly decrease the expression of?MDR1?and?MRP1?genes in C643 and SW1736 ATC cell lines. BI-847325 decreased multidrug resistance through downregulation of MDR1 and MRP1.

References

• Ref 1: The Novel ATP-Competitive MEK/Aurora Kinase Inhibitor BI-847325 Overcomes Acquired BRAF Inhibitor Resistance through Suppression of Mcl-1 and MEK ExpressionMol Cancer Ther. 2015 Jun;14(6):1354-64. doi: 10.1158/1535-7163.MCT-14-0832. Epub 2015 Apr 14.
• Ref 2: BI-847325, a selective dual MEK and Aurora kinases inhibitor, reduces aggressive behavior of anaplastic thyroid carcinoma on an in vitro three-dimensional culture. Cancer Cell Int. 2022 Dec 8;22(1):388.