Potent And-1 Inhibitors that Suppress Tumor Growth and Overcome Platinum Drug Resistance

Ovarian cancer (OC) 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. Recent studies showed that the Acidic nucleoplasmic DNA-binding protein 1 (And-1) activation promotes platinum drug resistance of OC. And-1 inhibitors re-sensitize platinum-resistant OC to platinum drugs.

GW and CAMS & PUMC researchers identified three potent And-1 inhibitors that inhibit cell growth of multiple cancer types and overcome platinum drug resistance of OC in vitro and in vivo. No systemic toxicity or side effects were observed. The researchers characterized the molecular mechanism of how And-1 inhibitors induce And-1 protein degradation via a proteasome degradation pathway. In addition to the novel And-1 inhibitors, the team also identified that Bazedoxifene Acetate, an FDA approved drug for vasomotor symptoms associated with menopause, can inhibit And-1.

Figure. Inhibitory effect of novel compounds (XIV, X and II) on growth of an ovarian cancer cell line.

Applications:

• Overcome platinum drug resistance in ovarian cancer
• Suppress tumor growth alone and in combination with platinum drugs
• Potential chemotherapy regimen to treat cancers and anti-cancer drug resistance

Advantages:

• Re-sensitize platinum-resistant OC to platinum drugs
• No systemic toxicity or side effects observed in mice
• Bazedoxifene Acetate has been approved by FDA
• Composition of matter intellectual property for new derivatives

Publication: 

• Li J, Zhang Y, Sun J, Chen L, Gou W, Chen CW, Zhou Y, Li Z, Chan DW, Huang R, Pei H, Zheng W, Li Y, Xia M, Zhu W. Discovery and characterization of potent And-1 inhibitors for cancer treatment. Clin Transl Med. 2021 Dec;11(12):e627. doi: 10.1002/ctm2.627. PMID: 34923765; PMCID: PMC8684776.