AK-2292 is a potent and selective STAT5 PROTAC degrader, with a DC50 of 0.10 μM. AK-2292 induces degradation of STAT5A/B proteins in vitro and in vivo. AK-2292 can induce tumor regression in acute myeloid leukemia and chronic myeloid leukemia xenograft mouse models. AK-2292 is a click chemistry reagent, it contains an Alkyne group and can undergo copper-catalyzed azide-alkyne cycloaddition (CuAAc) with molecules containing Azide groups.
AK-2292 (0.0015-15 μM; 4 days) inhibits the cell growth of SKNO1, MV4;11, and Kasumi-3 cells, with IC50s of 0.36, 0.35, and 0.18 μM, respectively[1].AK-2292 (0.008-5 μM; 18 h) reduces the levels of STAT5A, STAT5B and pSTAT5Y694 proteins in the SKNO1 cell line[1].AK-2292 (0.008-5 μM; 6 h) effectively reduces the levels of STAT5 and pSTAT5Y694 in the MV4;11 acute leukemia cell line[1].
AK-2292 (50-200 mg/kg; i.p. once a day, 5 days a week for 3 weeks) inhibits tumor growth in the MV4;11 xenograft model in mice[1].AK-2292 (150 mg/kg; a single i.p.) induces rapid and >95% depletion of STAT5 and pSTAT5Y694 proteins in the MV4;11 xenograft tissues in mice[1].AK-2292 (i.p.) exhibits good plasma exposure and has a plasma half-life of 1.9 h, moderate clearance (CL=0.77 L/h/kg), and good volume distribution (Vz=2.1 L/kg)[1].
References:
[1]. Kaneshige A, et, al. Discovery of a Potent and Selective STAT5 PROTAC Degrader with Strong Antitumor Activity In Vivo in Acute Myeloid Leukemia. J Med Chem. 2023 Feb 3.
[2]. Kaneshige A, et, al. A selective small-molecule STAT5 PROTAC degrader capable of achieving tumor regression in vivo. Nat Chem Biol. 2023 Feb 2.