Alobresib (GS-5829)

In-vitro experiments demonstrates high sensitivity of USC cell-lines to the exposure to GS-5829 causing a dose-dependent decrease in the phosphorylated levels of c-Myc and a dose-dependent increase in caspase activation (apoptosis).^[1] GS-5829 inhibits CLL cell proliferation and induces leukemia cell apoptosis through deregulation of key signaling pathways, such as BLK, AKT, ERK1/2, and MYC. IκBα modulation indicates that GS-5829 also inhibits NF-κB signaling. GS-5829-induced apoptosis results from an imbalance between positive (BIM) and negative regulators (BCL-XL) of the intrinsic apoptosis pathway.^[2]

TACS XTT cell proliferation/viability assay (Trevigen) is performed according to the manufacturer’s instructions on MEC-1 cells treated with GS-5829 or the BCR signaling inhibitors for 72 h. Half-maximal inhibitory concentrations (IC50) are calculated using Prism 6 or 7 based on technical triplicate measurements.

GS-5829 has impressive activity against USC primary tumors as well as USC xenografts. Assessment of c-Myc expression in tumors exposed to the GS-5829 demonstrates down-regulation of both total and phospho c-Myc proteins. GS-5829 demonstrates excellent bioavailability after oral administration and is significantly more effective than JQ1 at the doses used in comparative experiments in vivo against USC xenografts. Clinical studies with GS-5829 in USC patients harboring disease resistant to standard salvage chemotherapy are warranted.^[1]