Identification of three new compounds that directly target human serine hydroxymethyltransferase 2,Chemical Biology & Drug Design

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Identification of three new compounds that directly target human serine hydroxymethyltransferase 2
Chemical Biology & Drug Design ( IF 3.2 ) Pub Date : 2020-08-11 , DOI: 10.1111/cbdd.13774
Yanfang Han ₁ , Liping He ₁ , Yifei Qi _{1,

2} , Yue Zhao ₁ , Yue Pan ₁ , Bohuan Fang ₁ , Sha Li ₃ , John Z H Zhang _{1,

2,

4} , Lujia Zhang _{1,

2}

Affiliation

Mitochondrial serine hydroxymethyltransferase 2 (SHMT2) is an important drug target in the one‐carbon metabolic pathway, since its activity is critical for purine and pyrimidine biosynthesis. Additionally, it plays a prominent role during metabolic reprogramming of cancer cells, and SHMT2 inhibitors have proven useful as anticancer drugs. Compared to drugs targeting one‐carbon metabolic enzymes (mainly dihydrofolate reductase and thymidylate synthase) that have been used for clinical treatment of cancer, efficient SHMT2‐specific inhibitors are lacking. Therefore, we established a direct system for virtual screening, protein expression, and identification of inhibitors targeting SHMT2. First, 27 compounds qualifying as potential SHMT2 inhibitors were selected for biological activity verification through virtual screening of the 210 thousand compounds registered in the Specs database. Second, these 27 hits were subjected to quick screening by an in vitro non‐competitive kinetic assay of SHMT2 single‐enzyme catalysis. This allowed us to identify three compounds featuring medium‐strength and non‐competitive inhibition of SHMT2: AM‐807/42004511 (IC₅₀ = 14.52 ± 4.1665 μM), AM‐807/40675298 (IC₅₀ = 12.74 ± 5.8991 μM), and AM‐807/42004633 (IC₅₀ = 9.43 ± 0.5646 μM). We describe a quick screening method for the identification of inhibitors targeting SHMT2, providing a basis for subsequent identification and screening of new inhibitors.

中文翻译：

鉴定直接靶向人丝氨酸羟甲基转移酶 2 的三种新化合物

线粒体丝氨酸羟甲基转移酶 2 (SHMT2) 是单碳代谢途径中的重要药物靶点，因为其活性对嘌呤和嘧啶的生物合成至关重要。此外，它在癌细胞的代谢重编程过程中发挥着重要作用，并且 SHMT2 抑制剂已被证明可用作抗癌药物。与已用于癌症临床治疗的靶向单碳代谢酶（主要是二氢叶酸还原酶和胸苷酸合酶）的药物相比，缺乏有效的 SHMT2 特异性抑制剂。因此，我们建立了一个用于虚拟筛选、蛋白质表达和鉴定针对 SHMT2 的抑制剂的直接系统。第一的，通过对 Specs 数据库中注册的 21 万种化合物的虚拟筛选，选择了 27 种符合潜在 SHMT2 抑制剂的化合物进行生物活性验证。其次，通过 SHMT2 单酶催化的体外非竞争动力学分析对这 27 个命中进行了快速筛选。这使我们能够鉴定出三种具有中等强度和非竞争性 SHMT2 抑制的化合物：AM-807/42004511（IC₅₀ = 14.52 ± 4.1665 μM）、AM-807/40675298（IC ₅₀ = 12.74 ± 5.8991 μM）和 AM-807/42004633（IC ₅₀ = 9.43 ± 0.5646 μM）。我们描述了一种用于识别针对 SHMT2 的抑制剂的快速筛选方法，为后续识别和筛选新的抑制剂提供了基础。

更新日期：2020-08-11

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