Drug Information

Drug (ID: DG01635) and It's Reported Resistant Information

• Name: BAY1217389
• Synonyms: 1554458-53-5; BAY1217389; Bay 1217389; BAY-1217389; UNII-M964LB1114; M964LB1114; Benzamide, N-cyclopropyl-4-[6-(2,3-difluoro-4-methoxyphenoxy)-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl]-2-methyl-; N-cyclopropyl-4-[6-(2,3-difluoro-4-methoxyphenoxy)-8-(3,3,3-trifluoropropylamino)imidazo[1,2-b]pyridazin-3-yl]-2-methylbenzamide; N-Cyclopropyl-4-(6-(2,3-difluoro-4-methoxyphenoxy)-8-((3,3,3-trifluoropropyl)amino)imidazo[1,2-b]pyridazin-3-yl)-2-methylbenzamide; Benzamide, N-cyclopropyl-4-(6-(2,3-difluoro-4-methoxyphenoxy)-8-((3,3,3-trifluoropropyl)amino)imidazo(1,2-b)pyridazin-3-yl)-2-methyl-; N-cyclopropyl-4-[6-(2,3-difluoro-4-methoxyphenoxy)-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl]-2-methylbenzamide; CHEMBL4456085; SCHEMBL15555839; EX-A948; BDBM258444; BCP17401; NSC787026; s8215; ZINC221039372; CCG-265387; CS-6182; NSC-787026; HY-12859; FT-0700219; US9512130, 2; J-690208; 1-(6-Isoquinolinyl)-3-[2-oxo-2-(1-pyrrolidinyl)ethyl]urea
• Formula: 9
• IsoSMILES: CC1=C(C=CC(=C1)C2=CN=C3N2N=C(C=C3NCCC(F)(F)F)OC4=C(C(=C(C=C4)OC)F)F)C(=O)NC5CC5
• InChI: InChI=1S/C27H24F5N5O3/c1-14-11-15(3-6-17(14)26(38)35-16-4-5-16)19-13-34-25-18(33-10-9-27(30,31)32)12-22(36-37(19)25)40-21-8-7-20(39-2)23(28)24(21)29/h3,6-8,11-13,16,33H,4-5,9-10H2,1-2H3,(H,35,38)
• InChIKey: WNEILUNVMHVMPH-UHFFFAOYSA-N
• PubChem CID: 78320750

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

Brain cancer [ICD-11: 2A00]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Dual specificity protein kinase TTK (TTK) [1]

• Sensitive Disease: Glioblastoma multiforme [ICD-11: 2A00.03]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell autophagy; Inhibition; hsa04140
• In Vitro Model: U251-MG cells; Brain; Homo sapiens (Human); CVCL_0021
• Experiment for Molecule Alteration: Western blot assay
• Experiment for Drug Resistance: CCK8 assay; Colony formation assay
• Mechanism Description: Knockdown of TTK increased the sensitivity of GBM cells to TMZ treatment, while overexpression of TTK induced TMZ resistance. Two specific TTK inhibitors, BAY-1217389 and CFI-402257, significantly inhibited GBM cell proliferation and improved the growth-suppressive effect of TMZ. In addition, the knockdown of TTK decreased the autophagy levels of GBM cells. Inhibition of TTK using specific inhibitors could also suppress the autophagy process. Blocking autophagy using chloroquine (CQ) abolished the TMZ resistance function of TTK in GBM cells and in the mouse model.

Colon cancer [ICD-11: 2B90]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Catenin beta-1 (CTNNB1) [2]

• Sensitive Disease: Colon cancer [ICD-11: 2B90.1]
• Molecule Alteration: IF-deletion; p.S45delS (c.133_135delTCT)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: SW48 cells; Colon; Homo sapiens (Human); CVCL_1724
• In Vitro Model: TOV-21G cells; Ovary; Homo sapiens (Human); CVCL_3613
• In Vitro Model: HuTu80 cells; Small intestine; Homo sapiens (Human); CVCL_1301
• In Vitro Model: TOV-112D cells; Ovary; Homo sapiens (Human); CVCL_3612
• In Vitro Model: LS 174T cells; Colon; Homo sapiens (Human); CVCL_1384
• In Vitro Model: A427 cells; Lung; Homo sapiens (Human); CVCL_1055
• In Vivo Model: Mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Gene set analysis
• Experiment for Drug Resistance: Cell proliferation assay
• Mechanism Description: The if-deletion p.S45delS (c.133_135delTCT) in gene CTNNB1 cause the sensitivity of BAY1217389 by unusual activation of pro-survival pathway.

Colorectal cancer [ICD-11: 2B91]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Catenin beta-1 (CTNNB1) [2]

• Sensitive Disease: Colorectal cancer [ICD-11: 2B91.1]
• Molecule Alteration: Missense mutation; p.S45F (c.134C>T)
• Wild Type Structure: Method: X-ray diffraction; Resolution: 2.20 Å; PDB: 6O9B
• Mutant Type Structure: Method: X-ray diffraction; Resolution: 2.45 Å; PDB: 6O9C

RMSD: 0.23; TM score: 0.84883; Amino acid change: S45F

• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: SW48 cells; Colon; Homo sapiens (Human); CVCL_1724
• In Vitro Model: TOV-21G cells; Ovary; Homo sapiens (Human); CVCL_3613
• In Vitro Model: HuTu80 cells; Small intestine; Homo sapiens (Human); CVCL_1301
• In Vitro Model: TOV-112D cells; Ovary; Homo sapiens (Human); CVCL_3612
• In Vitro Model: LS 174T cells; Colon; Homo sapiens (Human); CVCL_1384
• In Vitro Model: A427 cells; Lung; Homo sapiens (Human); CVCL_1055
• In Vivo Model: Mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Gene set analysis
• Experiment for Drug Resistance: Cell proliferation assay
• Mechanism Description: The missense mutation p.S45F (c.134C>T) in gene CTNNB1 cause the sensitivity of BAY1217389 by unusual activation of pro-survival pathway

Key Molecule: Catenin beta-1 (CTNNB1) [2]

• Sensitive Disease: Colorectal cancer [ICD-11: 2B91.1]
• Molecule Alteration: Missense mutation; p.S33Y (c.98C>A)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: SW48 cells; Colon; Homo sapiens (Human); CVCL_1724
• In Vitro Model: TOV-21G cells; Ovary; Homo sapiens (Human); CVCL_3613
• In Vitro Model: HuTu80 cells; Small intestine; Homo sapiens (Human); CVCL_1301
• In Vitro Model: TOV-112D cells; Ovary; Homo sapiens (Human); CVCL_3612
• In Vitro Model: LS 174T cells; Colon; Homo sapiens (Human); CVCL_1384
• In Vitro Model: A427 cells; Lung; Homo sapiens (Human); CVCL_1055
• In Vivo Model: Mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Gene set analysis
• Experiment for Drug Resistance: Cell proliferation assay
• Mechanism Description: The missense mutation p.S33Y (c.98C>A) in gene CTNNB1 cause the sensitivity of BAY1217389 by unusual activation of pro-survival pathway

Lung cancer [ICD-11: 2C25]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Catenin beta-1 (CTNNB1) [2]

• Sensitive Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Molecule Alteration: Missense mutation; p.T41A (c.121A>G)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: SW48 cells; Colon; Homo sapiens (Human); CVCL_1724
• In Vitro Model: TOV-21G cells; Ovary; Homo sapiens (Human); CVCL_3613
• In Vitro Model: HuTu80 cells; Small intestine; Homo sapiens (Human); CVCL_1301
• In Vitro Model: TOV-112D cells; Ovary; Homo sapiens (Human); CVCL_3612
• In Vitro Model: LS 174T cells; Colon; Homo sapiens (Human); CVCL_1384
• In Vitro Model: A427 cells; Lung; Homo sapiens (Human); CVCL_1055
• In Vivo Model: Mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Gene set analysis
• Experiment for Drug Resistance: Cell proliferation assay
• Mechanism Description: The missense mutation p.T41A (c.121A>G) in gene CTNNB1 cause the sensitivity of BAY1217389 by unusual activation of pro-survival pathway

References

• Ref 1: TTK Protein Kinase promotes temozolomide resistance through inducing autophagy in glioblastoma. BMC Cancer. 2022 Jul 18;22(1):786.
• Ref 2: TTK Inhibitors as a Targeted Therapy for CTNNB1 (Beta-catenin) Mutant CancersMol Cancer Ther. 2017 Nov;16(11):2609-2617. doi: 10.1158/1535-7163.MCT-17-0342. Epub 2017 Jul 27.