Discovery of Selective Small Molecule Inhibitors of Monoacylglycerol Acyltransferase 3,Journal of Medicinal Chemistry

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Discovery of Selective Small Molecule Inhibitors of Monoacylglycerol Acyltransferase 3
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2015-09-08 00:00:00 , DOI: 10.1021/acs.jmedchem.5b01008
Kim Huard _{1,

2} , Allyn T. Londregan _{1,

2} , Gregory Tesz _{1,

2} , Kevin B. Bahnck _{1,

2} , Thomas V. Magee _{1,

2} , David Hepworth _{1,

2} , Jana Polivkova _{1,

2} , Steven B. Coffey _{1,

2} , Brandon A. Pabst _{1,

2} , James R. Gosset _{1,

2} , Anu Nigam _{1,

2} , Kou Kou _{1,

2} , Hao Sun _{1,

2} , Kyuha Lee _{1,

2} , Michael Herr _{1,

2} , Markus Boehm _{1,

2} , Philip A. Carpino _{1,

2} , Bryan Goodwin _{1,

2} , Christian Perreault _{1,

2} , Qifang Li _{1,

2} , Csilla C. Jorgensen _{1,

2} , George T. Tkalcevic _{1,

2} , Timothy A. Subashi _{1,

2} , Kay Ahn _{1,

2}

Affiliation

Inhibition of triacylglycerol (TAG) biosynthetic enzymes has been suggested as a promising strategy to treat insulin resistance, diabetes, dyslipidemia, and hepatic steatosis. Monoacylglycerol acyltransferase 3 (MGAT3) is an integral membrane enzyme that catalyzes the acylation of both monoacylglycerol (MAG) and diacylglycerol (DAG) to generate DAG and TAG, respectively. Herein, we report the discovery and characterization of the first selective small molecule inhibitors of MGAT3. Isoindoline-5-sulfonamide (6f, PF-06471553) selectively inhibits MGAT3 with high in vitro potency and cell efficacy. Because the gene encoding MGAT3 (MOGAT3) is found only in higher mammals and humans, but not in rodents, a transgenic mouse model expressing the complete human MOGAT3 was used to characterize the effects of 6f in vivo. In the presence of a combination of diacylglycerol acyltransferases 1 and 2 (DGAT1 and DGAT2) inhibitors, an oral administration of 6f exhibited inhibition of the incorporation of deuterium-labeled glycerol into TAG in this mouse model. The availability of a potent and selective chemical tool and a humanized mouse model described in this report should facilitate further dissection of the physiological function of MGAT3 and its role in lipid homeostasis.

中文翻译：

发现单酰基甘油酰基转移酶3的选择性小分子抑制剂。

有人提出抑制三酰甘油（TAG）生物合成酶是治疗胰岛素抵抗，糖尿病，血脂异常和肝脂肪变性的一种有前途的策略。单酰基甘油酰基转移酶3（MGAT3）是一种完整的膜酶，可催化单酰基甘油（MAG）和二酰基甘油（DAG）的酰化作用，分别生成DAG和TAG。在本文中，我们报道了MGAT3的第一个选择性小分子抑制剂的发现和表征。异吲哚啉-5-磺酰胺（6f，PF-06471553）选择性抑制MGAT3，具有很高的体外效力和细胞效力。因为仅在高等哺乳动物和人类中发现了编码MGAT3（MOGAT3）的基因，但在啮齿动物中却没有发现，所以表达完整人类MOGAT3的转基因小鼠模型用于表征6f在体内的作用。在二酰基甘油酰基转移酶1和2（DGAT1和DGAT2）抑制剂联合存在的情况下，口服6f在该小鼠模型中对氘标记的甘油掺入TAG表现出抑制作用。本报告中描述的有效且选择性的化学工具和人源化小鼠模型的可用性应有助于进一步剖析MGAT3的生理功能及其在脂质稳态中的作用。

更新日期：2015-09-08

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