Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, Research Center for Drug Discovery at School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, 510006, China.
Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, Research Center for Drug Discovery at School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, 510006, China.
Eur J Med Chem. 2020 May 15;194:112240. doi: 10.1016/j.ejmech.2020.112240. Epub 2020 Mar 17.
Discovery and optimization of selective liver X receptor β (LXRβ) agonists are challenging due to the high homology of LXRα and LXRβ in the ligand-binding domain. There is only one different residue (Val versus Ile) at the ligand-binding pocket of LXRs. With machine learning methods, we identified pan LXR agonists with a novel scaffold (spiro[pyrrolidine-3,3'-oxindole]). Then, we figured out the mechanism of LXR isoform selectivity from co-crystal structures. Based on the mechanism and the new scaffold, LXRβ selective agonists were designed and synthesized. This led to the discovery of LXRβ agonists 4-7rr, 4-13 and 4-13rr with IC values ranging from 1.78 to 6.36 μM against glioblastoma in vitro. Treatment with 50 mg/kg/day of 4-13 for 15 days significantly reduced tumor growth using an in vivo xenograft glioblastoma model.
由于肝 X 受体（LXR）α和 LXRβ在配体结合域具有高度同源性，因此发现和优化选择性 LXRβ激动剂具有挑战性。在 LXR 的配体结合口袋中只有一个不同的残基（缬氨酸对异亮氨酸）。通过机器学习方法，我们确定了具有新型骨架（螺吡咯烷-3,3'-恶吲哚）的 pan LXR 激动剂。然后，我们从共晶结构中找出了 LXR 同工型选择性的机制。基于该机制和新型骨架，设计并合成了 LXRβ选择性激动剂。这导致发现了 LXRβ激动剂 4-7rr、4-13 和 4-13rr，它们在体外对神经胶质瘤的 IC 值范围为 1.78 至 6.36μM。使用体内异种移植神经胶质瘤模型，每天用 50mg/kg 的 4-13 治疗 15 天，显著降低了肿瘤生长。
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