ZB716

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ZB716 structure

ZB716: An Orally Active Anti-Estrogenic Compound[edit | edit source]

ZB716, scientifically termed as fulvestrant-3-boronic acid, represents a state-of-the-art synthetic, steroidal antiestrogen. Its development specifically targets the treatment of estrogen receptor (ER)-positive metastatic breast cancer. As a potent and selective estrogen receptor degrader (SERD), ZB716 showcases a unique pharmacological profile compared to its parent compound, fulvestrant, paving the way for novel therapeutic approaches.

Chemical Structure and Mechanism[edit | edit source]

ZB716 can be best described as an analogue of fulvestrant. The main distinguishing feature between the two is the replacement of the C3 hydroxyl group in fulvestrant with a boronic acid moiety in ZB716[1]. This modification has noteworthy implications for the drug's pharmacokinetic properties and its route of administration.

  • Mechanism of Action: ZB716 functions as a silent antagonist of the ERα with an IC50 value of 4.1 nM, denoting its high potency in inhibiting estrogen receptor activity. Additionally, as a SERD, it promotes degradation of the estrogen receptor.

Pharmacokinetics and Administration[edit | edit source]

ZB716's modification offers an advantage over fulvestrant when it comes to bioavailability and administration:

  • Oral Activity: Unlike fulvestrant, which necessitates intramuscular injection due to its lack of oral activity, ZB716 is orally active. This can be attributed to its reduced susceptibility to first-pass metabolism.
  • Bioavailability: In mouse models, an oral dose of 8.3 mg/kg ZB716 results in a maximal blood concentration surpassing 160 ng/mL. Comparatively, subcutaneous injection of fulvestrant in mice achieves a concentration of just 15.2 ng/mL. This suggests that ZB716, when translated to human use, might not only be more convenient but could also provide superior systemic exposure and potentially enhanced therapeutic benefits.

Metabolic Profile[edit | edit source]

Upon administration, ZB716 undergoes metabolic transformations:

  • Fulvestrant as Metabolite: ZB716 is metabolized to produce fulvestrant in vivo in mice. Around 10-15% of ZB716 gets converted into fulvestrant, suggesting that the majority of the therapeutic effect can be attributed to the parent compound, ZB716.

Potential Therapeutic Implications[edit | edit source]

ZB716's pharmacological properties and enhanced bioavailability suggest potential advantages over fulvestrant:

  • Treatment of ER-Positive Metastatic Breast Cancer: Given its potent antiestrogenic activity and improved pharmacokinetics, ZB716 could offer a more effective treatment option for patients with ER-positive metastatic breast cancer.
  • Convenience and Compliance: The oral activity of ZB716 might lead to better patient compliance and convenience compared to intramuscular injections required for fulvestrant.

Future Perspectives[edit | edit source]

While ZB716 showcases promising in vitro and in vivo results, further clinical trials are imperative to validate its safety, efficacy, and therapeutic advantages over existing treatments.

ZB716 Resources

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Contributors: Prab R. Tumpati, MD