Fulvestrant-3 Boronic Acid (ZB716): An Orally Bioavailable Selective Estrogen Receptor Downregulator (SERD)

Liu, Jiawang; Zheng, Shilong; Akerstrom, Victoria; Yuan, Chester; Ma, Yueming; Zhong, Qi; Zhang, Changde; Zhang, Qiang; Guo, Shanchun; Ma, Peng; Skripnikova, Elena; Bratton, Melyssa R.; Pannuti, Antonio; Miele, Lucio; Wiese, Thomas E.; Wang, Guangdi

doi:10.1021/acs.jmedchem.6b00753

Cited by 69 publications

(86 citation statements)

References 35 publications

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“…While effective, each is not fully optimal, and some troubling side effects that may limit their clinical utility have been noted (8). RAD-0910 (40,41) and boronic acid derivatives of Fulvestrant and GW7604 (42,43) show promise, but clinical evaluations are at very early stages. Thus, there is an unmet need for orally active antiestrogens with an improved clinical profile and reduced side effects.…”

Section: Discussionmentioning

confidence: 99%

Structurally Novel Antiestrogens Elicit Differential Responses from Constitutively Active Mutant Estrogen Receptors in Breast Cancer Cells and Tumors

et al. 2017

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Many ERα-positive breast cancers develop resistance to endocrine therapy via mutation of estrogen receptors (ER) whose constitutive activation is associated with shorter patient survival. Because there is now a clinical need for new antiestrogens (AE) against these mutant ER, we describe here our development and characterization of three chemically novel AE that effectively suppress proliferation of breast cancer cells and tumors. Our AE are effective against wild type and Y537S and D538G ER, the two most commonly occurring constitutively active ER. The 3 new AE suppressed proliferation and estrogen target gene expression in WT and mutant ER-containing cells and were more effective in D538G than in Y537S cells and tumors. Compared to WT ER, mutants exhibited ~10 to 20-fold lower binding affinity for AE and a reduced ability to be blocked in coactivator interaction, likely contributing to their relative resistance to inhibition by AE. Comparisons between mutant ER-containing MCF7 and T47D cells revealed that AE responses were compound, cell-type and ERα-mutant dependent. These new ligands have favorable pharmacokinetic properties and effectively suppressed growth of WT and mutant ER-expressing tumor xenografts in NOD/SCID-gamma mice after oral or subcutaneous administration; D538G tumors were more potently inhibited by AE than Y537S tumors. These studies highlight the differential responsiveness of the mutant ER to different AE and make clear the value of having a toolkit of AE for treatment of endocrine therapy-resistant tumors driven by different constitutively active ER.

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Section: Discussionmentioning

confidence: 99%

Structurally Novel Antiestrogens Elicit Differential Responses from Constitutively Active Mutant Estrogen Receptors in Breast Cancer Cells and Tumors

et al. 2017

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“…Its structure is liable to metabolism at C3 and C17 of its steroidal nucleus resulting in rapid deactivation. Chemical modification at C3 by addition of boronic acid yielded the new compound ZB716 with improved metabolic stability (Figure ) . Compounds containing an acetate group are liable to metabolism through de‐acetylation.…”

Section: Effect Of Chemical Structure On Physicochemical Properties Amentioning

confidence: 99%

“…Metabolic stability can be enhanced by alteration of the chemical structure. Example of this is blocking the metabolism liable site and chemical derivatization of small molecules. The substitution of l ‐amino acids by d ‐amino acids and the N ‐methylation in amino acids and peptides can be done to improve stability of peptide‐based therapeutics …”

Section: Chemical and Pharmaceutical Solutionsmentioning

confidence: 99%

Chemical structure modifications and nano‐technology applications for improving ADME‐Tox properties, a review

Farouk

Shamma

2019

Archiv der Pharmazie

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The chemical structure of a drug molecule affects its physicochemical properties and subsequent biological activities. Many pharmacologically active molecules fail to reach the market or have an inconvenient route of administration due to their chemical structure. This is especially important with the recent tendency to develop drug candidates beyond the drug-likeness space for addressing difficult targets such as protein-protein interfaces. The objective of this review is to discuss chemical and pharmaceutical approaches for circumventing structure-related problems and achieving acceptable ADME-Tox properties. The chemical structure-associated limitations are critically discussed. Chemical modifications and pharmaceutical technology applications for improving drug-likeness are illustrated. Attention is paid to modern therapeutic candidates and targets. In conclusion, chemical modifications as well as nanotechnology applications can be used effectively to enhance absorption, permeability, and selective distribution to a body compartment, to improve drug specificity, to limit off-target toxicity as well as to enhance stability and to protect against metabolism. The nano-technology-based solutions are relatively easier to develop over a new molecular entity, but adopting the chemical approach is more established in terms of safety, quality control, and regulatory assessment methods. K E Y W O R D Sblood-brain barrier, cancer tissue delivery, drug delivery, drug targeting, protein-protein interaction

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“…11,12) Boronic acids and esters emerged recently as biocompatible bioisosters and prodrugs of phenolic alcohols with enhanced bioavailability and selectivity. [13][14][15][16] Jiang et al showed that boronic derivatives of tamoxifen, the first line therapy in estrogen receptor positive (ER+) breast cancer, inhibit the growth of (ER+) breast cancer cell lines with potencies comparable to or greater than that of the parent drug, 4-hydroxytamoxifen. Moreover, those analogues were taken up by cancerous cells up to 4 times more efficiently than the parent phenol.…”

Section: Introductionmentioning

confidence: 99%

“…Moreover, those analogues were taken up by cancerous cells up to 4 times more efficiently than the parent phenol. 13) The aim of this work is to develop boronic derivatives of phenanthroindolizidine alkaloids and to evaluate their antiproliferative activity in-vitro. (R)-6-O-Desmethylantofine (1) was chosen as it is characterized by high cytotoxic activity and it possesses an amenable phenol functional group.…”

Section: Introductionmentioning

confidence: 99%

Boronic Analogues of (<i>R</i>)-6-<i>O</i>-Desmethylantofine as Anticancer Agents

Omran

Abdalla

Ibrahim

et al. 2019

CHEMICAL & PHARMACEUTICAL BULLETIN

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Phenanthroindolizidines are naturally occurring alkaloids mainly isolated from different species of Asclepiadaceae. These alkaloids are characterized by an excellent anticancer activity against a very wide range of cancerous cell lines including those who are multi drug resistant. Nevertheless, phenanthroindolizidines are associated with sever neurotoxicity that prevented any candidate from this family to pass the clinical trials. A number of boron-based analogues of (R)-6-O-desmethylantofine have been synthesised. Their physochemical properties were evaluated, same as their in-vitro antiproliferative activity. The pinacol boronate ester derivative (3) showed interesting cytotoxicity against a panel of cancerous cell lines attested by a cancer cell growth-inhibitory potency (GI 50) as low as 30 nM.

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Fulvestrant-3 Boronic Acid (ZB716): An Orally Bioavailable Selective Estrogen Receptor Downregulator (SERD)

Cited by 69 publications

References 35 publications

Structurally Novel Antiestrogens Elicit Differential Responses from Constitutively Active Mutant Estrogen Receptors in Breast Cancer Cells and Tumors

Structurally Novel Antiestrogens Elicit Differential Responses from Constitutively Active Mutant Estrogen Receptors in Breast Cancer Cells and Tumors

Chemical structure modifications and nano‐technology applications for improving ADME‐Tox properties, a review

Boronic Analogues of (<i>R</i>)-6-<i>O</i>-Desmethylantofine as Anticancer Agents

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