TUS-007

TUS-007 is a CANDDY molecular, modified from a proteasome inhibitor. However, TUS-007 hardly inhibits proteasome activity. TUS-007 is also an orally active and potent KRAS G12D/V degrader. TUS-007 can be applied in KRAS G12D/V chemical knockdown in cell-free. TUS-007 also exhibits tumor suppression[1]. Note: CANDDY refers to Chemical knockdown with Affinity aNd Degradation DYnamics.

Research Areas >> Cancer

Signaling Pathways >> GPCR/G Protein >> Ras

KRas G12D

KRas G12V

TUS-007 具有显著的靶向作用，对表达 KRAS G12D/V 的细胞具有毒性[1]。 TUS-007 (100 μM; 72 h) 选择性地降低表达 KRAS G12D/V 的低 RAS 小鼠胚胎成纤维细胞 (MEF) 的活力，而不是影响 KRAS G12C[1]。 TUS-007 (20-160 μM; 72 h) 可增加 annexin V 阳性的 SW1990 细胞的凋亡比例[1]。 Apoptosis Analysis[1] Cell Line: SW1990 cells Concentration: 20 μM, 40 μM, 80 μM, and 60 μM Incubation Time: 72 hours Result: Increased the proportion of annexin V-positive apoptotic SW1990 cells compared with those treated with DMSO or RAS-SOS-NH2.

TUS-007 (80 mg/kg 腹腔注射或 160 mg/kg 口服；每 3 天 1 次，共 21 天) 在 SW620-Luc 异种移植小鼠模型中，对 KRAS G12V 驱动的肿瘤在体内有抑制效力[1]。 TUS-007 即使在原位异种移植模型小鼠中也具有抗肿瘤活性[1]。 Animal Model: Immunodeficient mice bearing SW620-Luc cells[1] Dosage: 80 mg/kg or 160 mg/kg Administration: Intraperitoneal injection or oral gavage; once every 3 days for 21 days Result: Significantly attenuated tumor progression without affecting body weight.

[1]. Imanishi S, et al. In vivo KRAS G12D/V degradation mediated by CANDDY using a modified proteasome inhibitor. bioRxiv, 2021: 2021.04. 23.441075.