SD-36 is a potent and efficacious STAT3 PROTAC degrader (Kd=~50 nM), and demonstrates high selectivity over other STAT members. SD-36 also effectively degrades mutated STAT3 proteins in cells and suppresses the transcriptional activity of STAT3 (IC50=10 nM). SD-36 exerts robust anti-tumor activity, and achieves complete and long-lasting tumor regression in mouse tumor models. SD-36 is composed of the STAT3 inhibitor SI-109, a linker, and an analog of Cereblon ligand Lenalidomide for E3 ubiquitin ligase.IC50 & Target: Kd: ~50 nM (STAT3), 1-2 μM (STAT1 and STAT4), ~5 μM (STAT2 and STAT5A)In Vitro: SD-36 inhibits the growth of a subset of acute myeloid leukemia and anaplastic large-cell lymphoma cell lines by inducing cell-cycle arrest and/or apoptosis.
SD-36 (0.005-5 μM; 4 days) demonstrates potent activity (IC50＜2 μM) in MOLM-16, DEL, Karpas-299, KI-JK, SU-DHL-I, SUP-M2 cell lines.
SD-36 (1 μM; 5 hours) completely depletes both monomeric and dimeric STAT3 protein in MOLM-16 cells.In Vivo: SD-36 (25-100 mg/kg; i.v.; weekly dosing for 4 weeks) achieves complete and long-lasting tumor regression in mice.
SD-36 effectively inhibits tumor growth at 25 and 50 mg/kg administered on day 1, 3, and 5 per week and achieved complete tumor regression at 100 mg/kg with the same schedule in the SU-DHL-1 xenograft model.
SD-36 at 50 mg/kg 3 times per week completely inhibits tumor growth in the SUP-M2 tumor model.