RCMI Cancer Research Center, Xavier University of Louisiana, New Orleans, LA, 70125, USA.
Department of Pharmaceutical Sciences, University of Tennessee Health Sciences Center, Memphis, TN, 38163, USA.
Breast Cancer Res Treat. 2020 Apr;180(2):359-368. doi: 10.1007/s10549-020-05558-w. Epub 2020 Feb 6.
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.
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.
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 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. To test the in vivo efficacy of GLL398, mice bearing MCF-7-derived xenograft breast tumors and patient-derived xenograft tumors harboring ER were treated with GLL398 which potently inhibited tumor growth in mice.
This study demonstrates GLL398 is an oral SERD that has therapeutic efficacy in clinically relevant breast tumor models.
自 2002 年 FDA 批准氟维司群以来，选择性雌激素受体降解剂（SERD）已被证明在治疗晚期或转移性乳腺癌方面具有临床疗效。最近，其适应证不断扩大，包括一线单药治疗以及与 CDK4/6 抑制剂联合治疗，进一步扩展了其作为有效乳腺癌内分泌治疗方案的临床应用。然而，氟维司群的药代动力学特性差及其仅注射给药途径促使人们不断努力开发口服生物利用度的 SERD，这可能会提高对 SERD 治疗的临床反应。硼修饰的 GW5638 类似物 GLL398 表现出优异的口服生物利用度，同时保留了抗雌激素活性和 ER 降解功效，其效力水平与 GW5638 的更活跃代谢物 GW7604 相当。
在这里，我们使用分子建模、ER（Y537S）结合测定、MCF-7 异种移植肿瘤和患者来源的异种移植（PDX）肿瘤模型，对 GLL398 的药理学和代谢进行了进一步研究。
与 GLL398 在对他莫昔芬耐药或表达组成性激活的突变型 ESR1（Y537S）的乳腺癌细胞中的强大活性一致，它被发现与突变型 ER 具有高亲和力。GLL398 与 ER 结合模式的分子建模还发现其分子相互作用与实验确定的对 WT ER 和 ER 的高结合亲和力一致。为了测试 GLL398 的体内疗效，携带 MCF-7 衍生的异种移植乳腺癌肿瘤和携带 ER 的患者来源的异种移植肿瘤的小鼠用 GLL398 治疗，GLL398 有效地抑制了小鼠的肿瘤生长。
这项研究表明，GLL398 是一种口服 SERD，在临床上相关的乳腺癌肿瘤模型中具有治疗效果。
