Selective estrogen receptor degrader (SERD) has proven clinically effective in treating advanced or metastatic breast cancer since the approval of fulvestrant by FDA in 2002. Recent expansion of indications as a first line monotherapy and as combination therapy with CDK4/6 inhibitors further extends its clinical utility as an efficacious breast cancer endocrine regimen. However, the poor pharmacokinetic properties of fulvestrant and its injection-only administration route has driven continued efforts to develop orally bioavailability SERD that could potentially improve clinical response to SERD treatment. GLL398, a boron-modified GW5638 analog, showed superior oral bioavailability, while retaining both antiestrogenic activity and ER degrading efficacy at a potency level comparable to the more active metabolite of GW5638, GW7604.

METHODS:

Here we used molecular modeling, ER (Y537S) binding assay, MCF-7 Xenograft tumor, and patient-derived xenograft (PDX) tumor model to conduct further studies on the pharmacology and metabolism of GLL398.

RESULTS:

Consistent with GLL398's robust activities in breast cancer cells that either are tamoxifen resistant or express constitutively active, mutant ESR1 (Y537S), it was found to bind the mutant ER^Y537S with high affinity. Molecular modeling of the binding mode of GLL398 to ER also found its molecular interactions consistent with the experimentally determined high binding affinity towards WT ER and ER^Y537S. To test the in vivo efficacy of GLL398, mice bearing MCF-7-derived xenograft breast tumors and patient-derived xenograft tumors harboring ER^Y537S were treated with GLL398 which potently inhibited tumor growth in mice.

CONCLUSIONS:

This study demonstrates GLL398 is an oral SERD that has therapeutic efficacy in clinically relevant breast tumor models.

2017-01-12·ACS medicinal chemistry letters3区 · 医学

Rational Design of a Boron-Modified Triphenylethylene (GLL398) as an Oral Selective Estrogen Receptor Downregulator

3区 · 医学

Article

作者: Liu, Jiawang ; Wang, Guangdi ; Guo, Shanchun ; Zheng, Shilong ; Zhang, Qiang ; Wiese, Thomas E ; Zhang, Changde ; Ma, Peng ; Zhong, Qiu ; Bratton, Melyssa R ; Skripnikova, Elena V

Development of orally bioavailable nonsteroidal selective estrogen receptor downregulators (SERDs) provides clinical opportunities for the long-term treatment and adjuvant therapy of breast cancer at all stages. We describe the design, synthesis, and identification of a boron-modified GW7604 derivative (GLL398, 9), a SERD candidate, in which a boronic acid functional group replaces the phenolic hydroxyl group of GW7604. Compound 9 strongly binds to ERα in a fluorescence resonance energy transfer binding assay (IC₅₀ = 1.14 nM) and potently degrades ERα in MCF-7 breast cancer cells (IC₅₀ = 0.21 μM). Most importantly, the introduction of the boronic acid group confers superior oral bioavailability of 9 (AUC = 36.9 μg·h/mL) in rats as compared to GW7604 (AUC = 3.35 μg·h/mL). The strikingly favorable pharmacokinetic property of 9 makes it a promising oral SERD suitable for clinical evaluation.

100 项与 GLL-398 相关的药物交易

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