Discovery of a Small Side Cavity in Sphingosine Kinase 2 that Enhances Inhibitor Potency and Selectivity.,Journal of Medicinal Chemistry

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Discovery of a Small Side Cavity in Sphingosine Kinase 2 that Enhances Inhibitor Potency and Selectivity.
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2020-01-02 , DOI: 10.1021/acs.jmedchem.9b01508
Christopher D Sibley ₁ , Emily A Morris ₁ , Yugesh Kharel ₂ , Anne M Brown _{3,

4} , Tao Huang ₂ , David R Bevan _{3,

4} , Kevin R Lynch ₂ , Webster L Santos _{1,

4}

Affiliation

The sphingosine-1-phosphate (S1P) signaling pathway is an attractive drug target due to its involvement in immune cell chemotaxis and vascular integrity. The formation of S1P is catalyzed by sphingosine kinase 1 or 2 (SphK1 or SphK2) from sphingosine (Sph) and ATP. Inhibition of SphK1 and SphK2 to attenuate levels of S1P has been reported to be efficacious in animal models of diseases such as cancer, sickle cell disease, and renal fibrosis. While inhibitors of both SphKs have been reported, improvements in potency and selectivity are still needed. Toward that end, we performed structure-activity relationship profiling of 8 (SLM6031434) and discovered a heretofore unrecognized side cavity that increased inhibitor potency toward SphK2. Interrogating this region revealed that relatively small hydrophobic moieties are preferred, with 10 being the most potent SphK2-selective inhibitor (Ki = 89 nM, 73-fold SphK2-selective) with validated in vivo activity.

中文翻译：

发现鞘氨醇激酶 2 中的小侧腔可增强抑制剂的效力和选择性。

1-磷酸鞘氨醇 (S1P) 信号通路是一个有吸引力的药物靶点，因为它参与免疫细胞趋化性和血管完整性。S1P 的形成由来自鞘氨醇 (Sph) 和 ATP 的鞘氨醇激酶 1 或 2（SphK1 或 SphK2）催化。据报道，抑制 SphK1 和 SphK2 以降低 S1P 水平在癌症、镰状细胞病和肾纤维化等疾病的动物模型中是有效的。虽然已经报道了两种 SphK 的抑制剂，但仍需要提高效力和选择性。为此，我们对 8 (SLM6031434) 进行了结构-活性关系分析，并发现了一个迄今为止未被识别的侧腔，它增加了对 SphK2 的抑制剂效力。询问该区域表明相对较小的疏水部分是首选，

更新日期：2020-01-29

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