SD-36是一种有效的PROTACSTAT3降解剂(Kd=~50nM)，与其他STAT成员相比具有很高的选择性。SD-36有效降解细胞中突变的STAT3蛋白，并抑制STAT3的转录活性(IC50=10nM)。SD-36发挥强大的抗肿瘤活性，并在小鼠肿瘤模型中实现了完整而持久的肿瘤消退。SD-36由STAT3抑制剂SI-109、linker和一个用于E3泛素连接酶的CRBN配体Lenalidomide类似物组成。
SD-36 is a potent and efficacious PROTAC STAT3 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 CRBN ligand Lenalidomide for E3 ubiquitin ligase[1].
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[1].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[1].SD-36 (1 μM; 5 hours) completely depletes both monomeric and dimeric STAT3 protein in MOLM-16 cells[1]. Cell Viability Assay[1] Cell Line: MOLM-16, DEL, Karpas-299, KI-JK, SU-DHL-I, SUP-M2 cell lines
SD-36 (25-100 mg/kg; i.v.; weekly dosing for 4 weeks) achieves complete and long-lasting tumor regression in mice[1].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[1].SD-36 at 50 mg/kg 3 times per week completely inhibits tumor growth in the SUP-M2 tumor model[1]. Animal Model: SCID female mice (MOLM-16 xenograft model)[1]
[1]. Bai L, et al. A Potent and Selective Small-Molecule Degrader of STAT3 Achieves Complete Tumor Regression In Vivo. Cancer Cell. 2019 Nov 11;36(5):498-511.e17.
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