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Biological Activity:
TG101348 is a potent, specific and orally bioavailable inhibitor of JAK2 (IC₅₀ ~3 nM) and BRD4 (IC₅₀ ~164 nM). It is 35- and 334-fold more selective for JAK2 versus JAK1 and JAK3. It also significantly inhibits JAK2 V617F, Flt3, and Ret with IC50 of 3 nM, 15 nM, and 48 nM, respectively. TG101348 induces apoptosis in both HEL and Ba/F3 JAK2V617F cells, but not in normal human dermal fibroblasts at concentrations up to 10 uM, and its antiproliferative IC₅₀ against fibroblasts is > 5 uM. In a UT7/EPO cell line, TG101348 inhibited STAT5 phosphorylation at 600 nM and inhibited AKT phosphorylation while reducing GATA-1 S310 phosphorylation. It also displaces BRD4 from chromatin and suppresses c-Myc expression. The combination of inhibitory activities on independent kinase and bromodomain oncogenic pathways exemplifies a new strategy for rational single-agent polypharmacological targeting.