Chronic myeloid leukemia (CML) is a myeloproliferative disorder characterized by the presence of the oncogenic fusion protein BCR-ABL1, the product of a translocation of chromosomes 9 and 22. This fusion results in a constitutively active BCR-ABL1 kinase that drives the overproduction and expansion of white blood cells in the bone marrow, and ultimately crowds out normal cells present in the bone marrow niche. GMB-475 is a degrader of BCR-ABL1 tyrosine kinase based on PROTAC. GMB-475 induced the degradation of BCR-ABL1 and c-ABL1 in the context of both human K562 cells and murine BCR-ABL1 transformed Ba/F3 cells with concomitant inhibition of downstream signaling via the STAT5 pathway, in a dose- and time-dependent fashion (human and murine VHL (Von Hippel Lindau) share >70% identity). In both cases, GMB-475 was capable of inhibiting cell proliferation with an IC50 of approximately 1 μM. Co-treatment of K562 cells with the proteasome inhibitor epoxomicin and GMB-475 restored the levels of BCR-ABL1 and c-ABL1 compared to GMB-475 alone. Dose response titration was performed with BCR-ABL1 transformed Ba/F3 cells for GMB-475 and IC50 value was 1.11 μM. Interestingly, cells bearing a G250E mutation in BCR-ABL1 were particularly susceptible to GMB-475 displaying enhanced antiproliferative activity[1].
搜索
