ZB716

ZB716 structure

ZB716: An Orally Active Anti-Estrogenic Compound

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

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

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

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

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

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.

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