Ovarian cancer is one of the leading causes of cancer-related deaths in women. The survival rate of ovarian cancer patients is low largely due to platinum-based chemotherapy resistance and lack of alternative regimens. A recent study indicated that Janus tyrosine kinase 2 (JAK2), which activates the signal transducers and activators of transcription (STAT) proteins in the cytoplasm and anti-apoptosis signaling is responsible for this platinum drug resistance. Multiple candidate drugs targeting JAK2 were discontinued in clinical trials due to toxicity and off-target effects. Finding a new target in the JAK2-STAT pathway could lead to more specific inhibition, an improved safety profile, and a way to overcome or prevent platinum drug resistance.
GW and CAMS & PUMC researchers discovered that the protease SENP1 regulates the kinase activity of JAK2 through deSUMOylation. SENP1-specific inhibitors were known, but not with high potency. The researchers identified ursolic acid as a potent SENP1 inhibitor which overcomes platinum drug resistance in ovarian cancer in vitro and in vivo. It inhibits SENP1 at a nanomolar level. Additionally, the team developed novel ursolic acid derivatives UAMMC-1, UAMMC-3 and UAMMC-9 which also inhibit SENP1 activity.
Figures: Tumor size from xenograft mice treated with control, cisplatin, UA, and UA+cisplatin.
Applications
- Overcome platinum drug resistance in ovarian cancer
- Suppress tumor growth
Advantages
- Increased specificity for JAK2-STAT pathway
- Synergistic effect with cisplatin
- Ursolic acid is a natural compound and is demonstrated to be safe based on clinical trials
- Composition of matter intellectual property for new derivatives
