TG101209

TG101209, an orally bioavailable JAK2 inhibitor potently inhibits myeloproliferative disorder-associated JAK2V617F and MPLW515L/K mutations. TG101209 potently inhibits JAK2 (IC(50)=6 nM), FLT3 (IC(50)=25 nM) and RET (IC(50)=17 nM) kinases, with significantly less activity against other tyrosine kinases including JAK3 (IC(50)=169 nM). TG101209 also inhibited STAT3 activation and survivin expression, and sensitized HCC2429 (DER=1.34, p=0.002) and H460 (DER=1.09, p=0.006) cells to radiation in clonogenic assays. In vivo, addition of TG101209 to radiation in lung xenografts produced a significant tumor growth delay (>10 days). TG101209 has significant in vitro activity in multiple myeloma and displays preferential cytotoxicity for CD45+ myeloma cells.