Department of Bioengineering, Stanford University, Stanford, CA, USA.
Department of Biology, Stanford University, Stanford, CA, USA.
Nat Commun. 2019 Mar 4;10(1):1033. doi: 10.1038/s41467-019-08965-w.
Taxanes are a family of natural products with a broad spectrum of anticancer activity. This activity is mediated by interaction with the taxane site of beta-tubulin, leading to microtubule stabilization and cell death. Although widely used in the treatment of breast cancer and other malignancies, existing taxane-based therapies including paclitaxel and the second-generation docetaxel are currently limited by severe adverse effects and dose-limiting toxicity. To discover taxane site modulators, we employ a computational binding site similarity screen of > 14,000 drug-like pockets from PDB, revealing an unexpected similarity between the estrogen receptor and the beta-tubulin taxane binding pocket. Evaluation of nine selective estrogen receptor modulators (SERMs) via cellular and biochemical assays confirms taxane site interaction, microtubule stabilization, and cell proliferation inhibition. Our study demonstrates that SERMs can modulate microtubule assembly and raises the possibility of an estrogen receptor-independent mechanism for inhibiting cell proliferation.
紫杉烷是一类具有广谱抗癌活性的天然产物。这种活性是通过与β-微管蛋白的紫杉烷结合位点相互作用介导的，导致微管稳定和细胞死亡。尽管紫杉烷类药物在乳腺癌和其他恶性肿瘤的治疗中得到了广泛应用，但现有的紫杉烷类药物治疗，包括紫杉醇和第二代多西紫杉醇，目前受到严重不良反应和剂量限制毒性的限制。为了发现紫杉烷类药物结合位点调节剂，我们采用了一种计算结合位点相似性筛选方法，对来自 PDB 的超过 14000 个类药性口袋进行筛选，揭示了雌激素受体和β-微管蛋白紫杉烷结合口袋之间出乎意料的相似性。通过细胞和生化测定评估了 9 种选择性雌激素受体调节剂（SERMs），证实了紫杉烷类药物结合位点的相互作用、微管稳定和细胞增殖抑制。我们的研究表明，SERMs 可以调节微管组装，并提出了一种雌激素受体非依赖性抑制细胞增殖的机制的可能性。
