| Identification | Back Directory | [Name]
GMB-475 | [CAS]
2490599-18-1 | [Synonyms]
GMB-475
(2S,4R)-1-((S)-3,3-Dimethyl-2-(2-(2-(4-(6-((4-(trifluoromethoxy)phenyl)amino)pyrimidin-4-yl)phenoxy)ethoxy)acetamido)butanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide | [Molecular Formula]
C43H46F3N7O7S | [MOL File]
2490599-18-1.mol | [Molecular Weight]
861.94 |
| Chemical Properties | Back Directory | [Boiling point ]
1029.7±65.0 °C(Predicted) | [density ]
1.337±0.06 g/cm3(Predicted) | [solubility ]
DMSO:145.4(Max Conc. mg/mL);168.69(Max Conc. mM)
Ethanol:50.0(Max Conc. mg/mL);58.01(Max Conc. mM) | [form ]
Solid | [pka]
13.50±0.46(Predicted) | [color ]
Light yellow to yellow | [InChIKey]
ONDVWISBMHHLGZ-XAYQSWBHNA-N | [SMILES]
C(N1C[C@H](O)C[C@H]1C(=O)NCC1C=CC(C2=C(N=CS2)C)=CC=1)(=O)[C@H](C(C)(C)C)NC(=O)COCCOC1C=CC(C2=NC=NC(NC3C=CC(OC(F)(F)F)=CC=3)=C2)=CC=1 |&1:3,6,24,r| |
| Hazard Information | Back Directory | [Description]
GMB-475 acts as a degrader of BCR-ABL 1 tyrosine kinase and as a recruiter of the E3 ligase Von Hippel Lindau (VHL) resulting in ubiquitination and subsequent degradation of oncogenic fusion proteins. | [Uses]
GMB-475 is a potent BCR-ABL1 PROTAC based on Von Hippel-Lindau (VHL). GMB-475 targets the nutmeg pocket of ABL1 in an ectopic manner and degrades BCR-ABL1 protein through the ubiquitin proteasome pathway. GMB-475 inhibits the proliferation of human K562 cells and mouse Ba/F3 cells, and is used for the study of chronic myeloid leukemia. (Blue: VHL ligand (HY-125845); Black: Linker; Pink: BCR-ABL1 ligand (HY-11007))[1][2]. | [Biological Activity]
GMB-475, a BCR-ABL1 Inhibitor Based on PROTAC, Has the Potential to Overcome BCR-ABL1-Dependent Drug Resistance. In both human CML K562 cells and murine Ba/F3 cells expressing BCR-ABL1, GMB-475 induces rapid proteasomal degradation and inhibition of downstream biomarkers. Notably, GMB-475 inhibits the proliferation of certain clinically relevant BCR-ABL1 kinase domain point mutants. GMB-475 reduces viability and increases apoptosis in primary chronic myeloid leukemia CD34+ cells, with no effect on healthy CD34+ cells. Furthermore, GMB-475 degrades BCR-ABL1 and reduces cell viability in primary chronic myeloid leukemia stem cells. | [in vivo]
GMB-475 (5 mg/kg; once every two days; 10 days; i.p.) improves chronic myeloid leukemia in mice with BCR::ABL1 mutant by targeted degradation of BCR-ABL1b and combined with dasatinib (HY-10181)[2]. | Animal Model: | 8-week-old Balb/c mice were injected with Ba/F3-MG-p210-Luc cells via tail vein to establish a chronic myeloid leukemia (CML) mouse model[2]. | | Dosage: | 5 mg/kg | | Administration: | Intraperitoneal injection (i.p.); once every two days; 10 days | | Result: | Showed a trend of reducing the tumor burden and prolonging the survival of the CML mouse model. |
| [IC 50]
STAT5; VHL; Bcr-Abl | [storage]
Store at -20°C | [References]
[1] Burslem GM, et al. Targeting BCR-ABL1 in Chronic Myeloid Leukemia by PROTAC-Mediated Targeted Protein Degradation. Cancer Res. 2019 Sep 15;79(18):4744-4753. DOI:10.1158/0008-5472.CAN-19-1236
[2] Ye W, et al. The proteolysis targeting chimera GMB-475 combined with dasatinib for the treatment of chronic myeloid leukemia with BCR::ABL1 mutants. Front Pharmacol. 2022 Oct 3;13:931772. DOI:10.3389/fphar.2022.931772 |
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