ZB716

ZB716, also known as fulvestrant-3-boronic acid, is a synthetic, steroidal, orally active antiestrogen which is under development for the treatment of estrogen receptor (ER)-positive metastatic breast cancer.[1] The drug is a silent antagonist of the ERα (IC50 = 4.1 nM) as well as a selective estrogen receptor degrader (SERD).[1] It is an analogue of fulvestrant in which the C3 hydroxyl group has been replaced with a boronic acid moiety.[1] In accordance, the two drugs have similar pharmacodynamic properties.[1] However, whereas fulvestrant is not orally active and must be administered via intramuscular injection, ZB716 is less susceptible to first-pass metabolism, and in relation to this, is orally active.[1]

ZB716
Clinical data
Other namesFulvestrant-3-boronic acid; Fulvestrant-3-boronoate; 7α-[9-[(4,4,5,5,5-Pentafluoropentyl)-sulfinyl]nonyl]-3-(dihydroxy-boryl)estra-1,3,5(10)-trien-17β-ol
Routes of
administration		By mouth[1]
Drug classAntiestrogen; Selective estrogen receptor degrader
Identifiers
IUPAC name
  • [(7R,8R,9S,13S,14S,17S)-17-hydroxy-13-methyl-7-[9-(4,4,5,5,5-pentafluoropentylsulfinyl)nonyl]-6,7,8,9,11,12,14,15,16,17-decahydrocyclopenta[a]phenanthren-3-yl]boronic acid
CAS Number
PubChem CID
UNII
Chemical and physical data
FormulaC32H48BF5O4S
Molar mass634.59 g·mol−1
3D model (JSmol)
Melting point230 °C (446 °F) (decomposes)
SMILES
  • B(C1=CC2=C(C=C1)[C@H]3CC[C@]4([C@H]([C@@H]3[C@@H](C2)CCCCCCCCCS(=O)CCCC(C(F)(F)F)(F)F)CC[C@@H]4O)C)(O)O
InChI
  • InChI=1S/C32H48BF5O4S/c1-30-17-15-26-25-12-11-24(33(40)41)21-23(25)20-22(29(26)27(30)13-14-28(30)39)10-7-5-3-2-4-6-8-18-43(42)19-9-16-31(34,35)32(36,37)38/h11-12,21-22,26-29,39-41H,2-10,13-20H2,1H3/t22-,26-,27+,28+,29-,30+,43?/m1/s1
  • Key:FIAYIYKWRBIBQG-GDWZZRAASA-N

A single oral dose of 8.3 mg/kg ZB716 to mice has been found to result in an over 160 ng/mL (160,000 pg/mL) maximal concentration of the drug in circulation, a level far in excess of the 15.2 ng/mL (15,200 pg/mL) concentration achieved with subcutaneous injection of fulvestrant in mice.[1] As such, not only may ZB716 be more convenient to administer in humans, it has far greater bioavailability compared to fulvestrant and hence may allow for greater systemic exposure and therapeutic benefit.[1]

ZB716 produces fulvestrant as an active metabolite in vivo in mice, with approximately 10 to 15% of the drug being converted into it.[1] As such, most of the effects are likely due to the parent drug.[1]

Clinical Development

As of December 2020, it is in a phase I clinical trial for ER+/HER2- metastatic breast cancer.[2]

See also

References
  1. Liu J, Zheng S, Akerstrom VL, Yuan C, Ma Y, Zhong Q, Zhang C, Zhang Q, Guo S, Ma P, Skripnikova EV, Bratton MR, Pannuti A, Miele L, Wiese TE, Wang G (2016). "Fulvestrant-3 Boronic Acid (ZB716): An Orally Bioavailable Selective Estrogen Receptor Downregulator (SERD)". J. Med. Chem. 59 (17): 8134–40. doi:10.1021/acs.jmedchem.6b00753. PMC 5499704. PMID 27529700.
  2. ClinicalTrials.gov: NCT04669587



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