Name: GMB-475
Brand: BOC Sciences
Rating: 5 (1 reviews)

Size

Price

Stock

Quantity

$--

In stock

Purity

≥95%

Solubility

Soluble in DMSO

Appearance

White Solid

Storage

Store at -20°C

Shipping

Room temperature in continental US; may vary elsewhere

IUPACName

(2S,4R)-1-[(2S)-3,3-dimethyl-2-[[2-[2-[4-[6-[4-(trifluoromethoxy)anilino]pyrimidin-4-yl]phenoxy]ethoxy]acetyl]amino]butanoyl]-4-hydroxy-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide

Synonyms

GMB 475; GMB475; (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

Boiling Point

1029.7±65.0°C at 760 Torr

Density

1.337±0.06 g/cm3

InChI Key

ONDVWISBMHHLGZ-SBJIGXGQSA-N

InChI

InChI=1S/C43H46F3N7O7S/c1-26-38(61-25-50-26)29-7-5-27(6-8-29)21-47-40(56)35-19-31(54)22-53(35)41(57)39(42(2,3)4)52-37(55)23-58-17-18-59-32-13-9-28(10-14-32)34-20-36(49-24-48-34)51-30-11-15-33(16-12-30)60-43(44,45)46/h5-16,20,24-25,31,35,39,54H,17-19,21-23H2,1-4H3,(H,47,56)(H,52,55)(H,48,49,51)/t31-,35+,39-/m1/s1

SMILES

O=C(NC(C(=O)N1CC(O)CC1C(=O)NCC=2C=CC(=CC2)C=3SC=NC3C)C(C)(C)C)COCCOC=4C=CC(=CC4)C=5N=CN=C(C5)NC6=CC=C(OC(F)(F)F)C=C6

Mechanism

Target: GMB-475 targets BCR-ABL1 fusion kinase and cellular ABL1 proteins.

Binding site: It binds the allosteric myristoyl pocket of the ABL1 kinase domain.

Mechanism of action: GMB-475 is a VHL-recruiting BCR-ABL1 PROTAC that targets ABL1 allosterically through the myristoyl pocket rather than the orthosteric ATP site. By linking an ABL1-recognition ligand to a von Hippel-Lindau E3 ligase ligand, GMB-475 induces proximity between BCR-ABL1 and VHL-containing ubiquitin ligase machinery, leading to ubiquitination and proteasomal degradation. This approach removes the oncogenic fusion protein and can suppress downstream STAT5 signaling in cellular models. GMB-475 is useful for studying degradation-based modulation of BCR-ABL1 signaling, kinase-domain resistance contexts, and combination strategies with ATP-site inhibitors.

Applications

• PROTAC-Mediated Kinase Degradation: GMB-475 is utilized in research to selectively degrade kinase proteins, providing insights into kinase-related signaling pathways and their roles in disease progression. This approach enables the study of kinase function by removing the protein of interest, offering a powerful tool for dissecting cellular mechanisms.

• Targeted Degradation in Cancer Research: Employing GMB-475 allows researchers to investigate the effects of degrading oncogenic proteins, aiding in the understanding of cancer cell biology. By selectively targeting and degrading specific proteins, scientists can explore novel therapeutic strategies and identify potential targets for drug development.

• Protein Homeostasis Studies: GMB-475 serves as a critical tool in studying protein homeostasis and turnover. By facilitating the controlled degradation of target proteins, researchers can observe the dynamics of protein stability and interactions within cellular systems, contributing to a deeper understanding of cellular regulation mechanisms.

• Validation of Protein Targets: Researchers use GMB-475 to validate the role of specific proteins in various biological processes by inducing their degradation. This approach helps confirm the involvement of target proteins in pathways of interest, aiding in the identification of potential biomarkers or therapeutic targets.

1. Targeting BCR-ABL1 in Chronic Myeloid Leukemia by PROTAC-Mediated Targeted Protein Degradation.

Burslem, G.M., Schultz, A.R., Bondeson, D.P., Eide, C.A., Savage Stevens, S.L., Druker, B.J. and Crews, C.M., 2019. Cancer research, 79(18), pp.4744-4753.

Although the use of ATP-competitive tyrosine kinase inhibitors of oncoprotein BCR-ABL1 has enabled durable responses in patients with chronic myeloid leukemia (CML), issues of drug resistance and residual leukemic stem cells remain. To test whether the degradation of BCR-ABL1 kinase could offer improved response, we developed a series of proteolysis-targeting chimera (PROTAC) that allosterically target BCR-ABL1 protein and recruit the E3 ligase Von Hippel-Lindau, resulting in ubiquitination and subsequent degradation of the oncogenic fusion protein. In both human CML K562 cells and murine Ba/F3 cells expressing BCR-ABL1, lead compound GMB-475 induced rapid proteasomal degradation and inhibition of downstream biomarkers, such as STAT5, and showed increased sensitivity compared with diastereomeric controls lacking degradation activity. Notably, GMB-475 inhibited the proliferation of certain clinically relevant BCR-ABL1 kinase domain point mutants and further sensitized Ba/F3 BCR-ABL1 cells to inhibition by imatinib, while demonstrating no toxicity toward Ba/F3 parental cells. Reverse phase protein array analysis suggested additional differences in levels of phosphorylated SHP2, GAB2, and SHC associated with BCR-ABL1 degradation. Importantly, GMB-475 reduced viability and increased apoptosis in primary CML CD34+ cells, with no effect on healthy CD34+ cells at identical concentrations. GMB-475 degraded BCR-ABL1 and reduced cell viability in primary CML stem cells. Together, these findings suggest that combined BCR-ABL1 kinase inhibition and protein degradation may represent a strategy to address BCR-ABL1-dependent drug resistance, and warrant further investigation into the eradication of persistent leukemic stem cells, which rely on neither the presence nor the activity of the BCR-ABL1 protein for survival.

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