Discovery of a Small Side Cavity in Sphingosine Kinase 2 that Enhances Inhibitor Potency and Selectivity.
Discovery of a Small Side Cavity in Sphingosine Kinase 2 that Enhances Inhibitor Potency and Selectivity.
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DOI：
10.1021/acs.jmedchem.9b01508
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发表时间：
2020-02-13
影响因子：
7.3
通讯作者：
Santos WL
中科院分区：
文献类型：
--
作者：
Sibley CD;Morris EA;Kharel Y;Brown AM;Huang T;Bevan DR;Lynch KR;Santos WL
鞘氨醇-1-磷酸（S1P）信号通路由于其参与免疫细胞趋化和血管完整性而成为一个有吸引力的药物靶点。鞘氨醇激酶1或2 （SphK1或SphK2）由鞘氨醇（Sph）和ATP催化形成S1P。据报道，抑制SphK1和2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SphKs的抑制剂，但仍然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，发现了一个迄今为止未被识别的侧腔，该侧腔增加了对SphK2的抑制剂效力。对该区域的研究显示，相对较小的疏水部分是首选的，其中10个是最有效的SphK2选择性抑制剂（Ki = 89 nM， 73倍SphK2选择性），具有有效的体内活性。
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 2 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. Towards that end, we performed a 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.
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影响因子：
64.5
作者：
Chipuk JE;McStay GP;Bharti A;Kuwana T;Clarke CJ;Siskind LJ;Obeid LM;Green DR
通讯作者：
Green DR
影响因子：
4.1
作者：
Schnute, Mark E.;McReynolds, Matthew D.;Nagiec, Marek M.
通讯作者：
Nagiec, Marek M.
DOI：
10.1124/jpet.115.225862
发表时间：
2015-10-01
影响因子：
3.5
作者：
Kharel, Yugesh;Morris, Emily A.;Lynch, Kevin R.
通讯作者：
Lynch, Kevin R.
影响因子：
2.7
作者：
Congdon, Molly D.;Childress, Elizabeth S.;Santos, Webster L.
通讯作者：
Santos, Webster L.
影响因子：
3.7
作者：
Kharel Y;Agah S;Huang T;Mendelson AJ;Eletu OT;Barkey-Bircann P;Gesualdi J;Smith JS;Santos WL;Lynch KR
通讯作者：
Lynch KR