Probing the substitution pattern of indole-based scaffold reveals potent and selective sphingosine kinase 2 inhibitors.
Probing the substitution pattern of indole-based scaffold reveals potent and selective sphingosine kinase 2 inhibitors.
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DOI：
10.1016/j.ejmech.2020.113121
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发表时间：
2021-02-15
影响因子：
6.7
通讯作者：
Santos WL
中科院分区：
文献类型：
--
作者：
Congdon M;Fritzemeier RG;Kharel Y;Brown AM;Serbulea V;Bevan DR;Lynch KR;Santos WL
鞘氨醇1-磷酸（S1 P）水平升高和鞘氨醇激酶亚型（SphK 1和SphK 2）表达增加与多种疾病状态有关，包括癌症、炎症、自身免疫等。因此，S1 P信号轴已成为药物发现的有吸引力的靶点。在动物模型中，SphK 1或SphK 2的选择性抑制已被证明可有效调节S1 P水平。虽然SphK 1抑制剂受到了广泛关注，但正在开发有效和选择性的SphK 2抑制剂。以前，我们的小组报道了一种基于萘的SphK 2选择性抑制剂SLC 5081308，其对hSphK 2的选择性约为hSphK 1的7倍，并且SphK 2 Ki值为1.0 μM。为了提高SphK 2的效力和选择性，我们设计、合成并评估了一系列衍生自SLC 5081308的基于吲哚的化合物。在研究了吲哚环周围的取代模式后，我们发现1，5-二取代促进了SphK 2底物结合位点的最佳结合和随后的酶活性抑制。我们的研究导致了SLC 5101465的鉴定（6 r，SphK 2 Ki = 90 nM，对SphK 2的选择性超过SphK 1的110倍）。分子模拟研究显示，与Val 308、Phe 548、His 556和Cys 533的关键非极性相互作用以及与Asp 211和Asp 308的氢键是SphK 2高抑制性和选择性的原因。
Elevated levels of sphingosine 1-phosphate (S1P) and increased expression of sphingosine kinase isoforms (SphK1 and SphK2) have been implicated in a variety of disease states including cancer, inflammation, autoimmunity, among others. Consequently, the S1P signaling axis has become an attractive target for drug discovery. Selective inhibition of either SphK1 or SphK2 has been demonstrated to be effective in modulating S1P levels in animal models. While SphK1 inhibitors have received much attention, the development of potent and selective SphK2 inhibitors are emerging. Previously, our group reported a SphK2 naphthalene-based selective inhibitor, SLC5081308, which displays approximately 7-fold selectivity for hSphK2 over hSphK1 and has a SphK2 Ki value of 1.0 μM. To improve SphK2 potency and selectivity, we designed, synthesized, and evaluated a series of indole-based compounds derived from SLC5081308. After investigating substitution patterns around the indole ring, we discovered that 1,5-disubstitution promoted optimal binding in the SphK2 substrate binding site and subsequent inhibition of enzymatic activity. Our studies led to the identification of SLC5101465 (6r, SphK2 Ki = 90 nM, >110 fold selective for SphK2 over SphK1). Molecular modeling studies revealed key nonpolar interactions with Val308, Phe548, His556, and Cys533 and hydrogen bonds with both Asp211 and Asp308 as responsible for the high SphK2 inhibition and selectivity.
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DOI：
10.1126/science.1176709
发表时间：
2009-09-04
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Hait NC;Allegood J;Maceyka M;Strub GM;Harikumar KB;Singh SK;Luo C;Marmorstein R;Kordula T;Milstien S;Spiegel S
通讯作者：
Spiegel S
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：
Kharel, Yugesh;Huang, Tao;Lynch, Kevin R.
通讯作者：
Lynch, Kevin R.
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：
4.8
作者：
Billich, A;Bornancin, F;Baumruker, T
通讯作者：
Baumruker, T