DDO3711

DDO3711, a PP5-recruiting phosphatase recruitment chimeras (PHORCs), is formed by connecting a small molecular apoptosis signal-regulated kinase 1 (ASK1) inhibitor to a PP5 activator through a chemical linker. DDO3711 specifically inhibits ASK1 (IC50 =164.1 nM) not ASK2 (IC50>20 μM). DDO3711 significantly dephosphorylates p-ASK1T838 by recruiting PP5 and shows the ASK1-dependent antiproliferative activity. DDO3711 has anti-cancer activity and has the potential for abnormally phosphorylated oncoproteins research[1].

Research Areas >> Cancer

Signaling Pathways >> MAPK/ERK Pathway >> MAP3K

ASK1:164.1 nM (IC50)

ASK2:>20 μM (IC50)

DDO3711 (15 μM; 24小时) 通过以 PP5 依赖性方式减少 p-ASK1T838，从而对胃癌细胞显示出抗增殖作用。DDO3711 不抑制 GES-1 细胞和 HGC-27 细胞的增殖[1]。 DDO3711 (5 μM; 1-24小时) 以浓度依赖性方式抑制 CDK4/6 和细胞周期蛋白 D1 的表达[1]。 DDO3711 (5-50 μM; 0.5-2 小时) 在体外和细胞中有效地使 p-ASK1T838 去磷酸化。DDO3711 浓度依赖性降低 p-JNK 和 p-p38 的水平[1]。 Cell Proliferation Assay[1] Cell Line: MKN45 cells Concentration: 15 μM Incubation Time: 24 h Result: Showed strong antiproliferative activity (IC50=0.5 μM). Cell Cycle Analysis[1] Cell Line: MKN45 cells Concentration: 5 μM Incubation Time: 1-24 h Result: Inhibited the expression of CDK4/6 and cyclin D1 in a concentration-dependent manner. Western Blot Analysis[1] Cell Line: MKN45 cells Concentration: 5, 25, 50 μM Incubation Time: 0.5-2 h Result: Could dephosphorylate p-ASK1T838 in a time- and concentration-dependent manner in vitro.

DDO3711 (20, 40 mg/kg; 腹腔给药; 每天; 持续 21 天)以剂量依赖性方式显着抑制肿瘤生长[1]。 Animal Model: Four-week-old BALB/c nude mice with MKN45 cells[1] Dosage: 20, 40 mg/kg Administration: IP; daily; for 21 days Result: Caused significant inhibition of tumor growth in a dose-dependent manner. Significantly decreased the level of p-ASK1T838.

[1]. Qiuyue Zhang, et al. Protein Phosphatase 5-Recruiting Chimeras for Accelerating Apoptosis-Signal-Regulated Kinase 1 Dephosphorylation with Antiproliferative Activity. J Am Chem Soc. 2022 Dec 22.