Fine-tuning of nitrogen-containing bisphosphonate esters that potently induce degradation of HMG-CoA reductase
Fine-tuning of nitrogen-containing bisphosphonate esters that potently induce degradation of HMG-CoA reductase
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微调含氮二膦酸酯，有效诱导 HMG-CoA 还原酶降解
DOI：
10.1016/j.bmc.2022.117145
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发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Ohgane Kenji
中科院分区：
文献类型：
--
作者：
Kawamura Kota;Yoshioka Hiromasa;Sato Chikako;Yajima Tomoko;Furuyama Yuuki;Kuramochi Kouji;Ohgane Kenji
3-羟基-3-甲基戊二酰辅酶A（HMG-CoA）还原酶是胆固醇生物合成途径中的限速酶，靶向该酶催化结构域的竞争性抑制剂，即所谓的他汀类药物，被广泛用于治疗高脂血症。膜结构域介导甾醇加速降解，这是一种翻译后负反馈机制，并且已经研究了触发这种降解的小分子作为替代治疗选择。预期此类策略提供优于催化位点抑制剂的益处，因为抑制导致酶的转录和翻译后上调，需要更高剂量的抑制剂并伴随增加严重不良反应（包括肌病）的风险。通过我们先前对SR 12813（一种诱导HMG-CoA还原酶降解的合成小分子）的研究，我们鉴定了含氮双膦酸酯SRP 3042作为高效HMG-CoA还原酶降解剂。在这里，我们进行了系统的构效关系研究，以优化其活性和理化性质，特别是侧重于亲脂性的降低。发现分子上的单取代叔丁基增加HMG-CoA还原酶降解活性，同时降低亲脂性，表明饱和烷基的单取代是平衡先导化合物的效力和亲脂性的有用策略。
3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase is the rate-limiting enzyme in the cholesterol biosynthetic pathway, and competitive inhibitors targeting the catalytic domain of this enzyme, so-called statins, are widely used for the treatment of hyperlipidemia. The membrane domain mediates the sterol-accelerated degradation, a post-translational negative feedback mechanism, and small molecules triggering such degradation have been studied as an alternative therapeutic option. Such strategies are expected to provide benefits over catalytic site inhibitors, as the inhibition leads to transcriptional and post-translational upregulation of the enzyme, necessitating a higher dose of the inhibitors and concomitantly increasing the risk of serious adverse effects, including myopathies. Through our previous study on SR12813, a synthetic small molecule that induces degradation of HMG-CoA reductase, we identified a nitrogen-containing bisphosphonate ester SRP3042 as a highly potent HMG-CoA reductase degrader. Here, we performed a systematic structure-activity relationship study to optimize its activity and physicochemical properties, specifically focusing on the reduction of lipophilicity. Mono-fluorination oftert-butyl groups on the molecules was found to increase the HMG-CoA reductase degradation activity while reducing lipophilicity, suggesting the mono-fluorination of saturated alkyl groups as a useful strategy to balance potency and lipophilicity of the lead compounds.