KT-333 is a potent, highly selective, heterobifunctional small molecule degrader of STAT3 for the treatment of a variety of STAT3-dependent pathologies, including hematologic malignancies and solid tumors.KT-333 specifically binds to STAT3 proteins at one end of the spectrum, and binds to the E3 ubiquitin ligase, VHL, at the other end.

KT-333 is a PROTAC targeting STAT3 with a VHL-dependent mechanism that is in Phase 1a/1b trials for the treatment of multiple diseases, including R/R B-cell and T-cell lymphomas, classical Hodgkin lymphoma (cHL), solid tumors (ST), and large granular lymphocytic leukemia/T-cell prolymphocytic leukemia (LGL-L/T-PLL).[1]

KT-333 ammonium, administered intravenously at doses of 5, 10, 15, and 45 mg/kg once a week for two weeks, exhibited dose-dependent antitumor activity. Mice receiving 5 mg/kg achieved 79.9% tumor growth inhibition (TGI), while complete tumor regression was observed in those given 10, 15, or 45 mg/kg, with effects lasting until the end of the study [1]. Similarly, KT-333 ammonium at 10, 20, and 30 mg/kg showed dose-dependent antitumor effects over the same administration schedule. Mice treated with 10 mg/kg exhibited 83.8% TGI, and complete tumor regression was seen at 20 or 30 mg/kg, with sustained effects [1].