Biol. | first PROTAC molecules to STAT5 proteins with high specificity: new in the treatment of chronic myeloid leukemia-- AK-2292

Signal transducer and activator of transcription 5 (STAT5) is an attractive therapeutic target, but successful targeting of STAT5 has proved to be difficult. Here we report the development of AK-2292 as a first, potent and selective small-molecule degrader of both STAT5A and STAT5B isoforms. AK-2292 induces degradation of STAT5A/B proteins with an outstanding selectivity over all other STAT proteins and more than 6,000 non-STAT proteins, leading to selective inhibition of STAT5 activity in cells. AK-2292 effectively induces STAT5 depletion in normal mouse tissues and human chronic myeloid leukemia (CML) xenograft tissues and achieves tumor regression in two CML xenograft mouse models at well-tolerated dose schedules. AK-2292 is not only a powerful research tool with which to investigate the biology of STAT5 and the therapeutic potential of selective STAT5 protein depletion and inhibition but also a promising lead compound toward ultimate development of a STAT5-targeted therapy

AK-2292 selectively depletes STAT5A/B proteins in cells a, Immunoblot analysis of KU812 cells treated with AK-2292, AK-305 or AK-2292Me at the indicated concentrations for 18 hours. Representative blots from at least n = 2 independent experiments are shown. b, Immunoblot analysis of PBMCs treated with AK-2292, AK-305 or AK-2292Me at the indicated concentrations for 18 hours. Representative blots from three independent experiments are shown. c, Immunoblot analysis of KU812 cells treated with AK-2292 under indicated concentrations and treatment time. Data represent at least n = 2 independent experiments. d, Cells were treated with AK-2292 as indicated for multiplexed quantitative proteomics analysis. P value: two-sided Student's t-test. Each experiment was performed in three biological replicates. Proteins with P values less than 0.05 (y axis) and fold changes greater than 2 (x axis) are colored in blu