2490599-18-1

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.

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].

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.

STAT5; VHL; Bcr-Abl

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[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