Guo Shanchun, Zhang Changde, Bratton Melyssa, Mottamal Madhusoodanan, Liu Jiawang, Ma Peng, Zheng Shilong, Zhong Qiu, Yang Lin, Wiese Thomas E, Wu Yong, Ellis Matthew J, Matossian Margarite, Burow Matthew E, Miele Lucio, Houtman René, Wang Guangdi
Department of Chemistry, Xavier University of Louisiana, New Orleans, LA 70125, USA.
RCMI Cancer Research Center, Xavier University of Louisiana, New Orleans, LA 70125, USA.
Oncotarget. 2018 Jan 8;9(6):6924-6937. doi: 10.18632/oncotarget.24023. eCollection 2018 Jan 23.
Advances in oral SERDs development so far have been confined to nonsteroidal molecules such as those containing a cinnamic acid moiety, which are in earlystage clinical evaluation. ZB716 was previously reported as an orally bioavailable SERD structurally analogous to fulvestrant. In this study, we examined the binding details of ZB716 to the estrogen receptor alpha (ERα) by computer modeling to reveal its interactions with the ligand binding domain as a steroidal molecule. We also found that ZB716 modulates ERα-coregulator interactions in nearly identical manner to fulvestrant. The ability of ZB716 to inhibit cell growth and downregulate ER expression in endocrine resistant, ERα mutant breast cancer cells was demonstrated. Moreover, in both the MCF-7 xenograft and a patient derived xenograft model, orally administered ZB716 showed superior efficacy in blocking tumor growth when compared to fulvestrant. Importantly, such enhanced efficacy of ZB716 was shown to be attributable to its markedly higher bioavailability, as evidenced in the final plasma and tumor tissue concentrations of ZB716 in mice where drug concentrations were found significantly higher than in the fulvestrant treatment group.
迄今为止，口服选择性雌激素受体降解剂（SERD）的研发进展一直局限于非甾体类分子，如那些含有肉桂酸部分的分子，这些分子正处于临床早期评估阶段。ZB716之前被报道为一种口服生物可利用的SERD，其结构与氟维司群类似。在本研究中，我们通过计算机建模研究了ZB716与雌激素受体α（ERα）的结合细节，以揭示其作为甾体分子与配体结合域的相互作用。我们还发现ZB716调节ERα-共调节因子相互作用的方式与氟维司群几乎相同。证明了ZB716在内分泌耐药、ERα突变的乳腺癌细胞中抑制细胞生长和下调ER表达的能力。此外，在MCF-7异种移植模型和患者来源的异种移植模型中，与氟维司群相比，口服给药的ZB716在阻断肿瘤生长方面显示出更高的疗效。重要的是，ZB716这种增强的疗效被证明归因于其显著更高的生物利用度，这在小鼠的最终血浆和肿瘤组织浓度中得到证明，其中发现ZB716的药物浓度明显高于氟维司群治疗组。
