Design, Synthesis, and Evaluation of Lactate Dehydrogenase Inhibitors

描述（由申请人提供）：本文提出的工作目的是开发人酶乳酸脱氢酶A（LDH-A）的新型抑制剂。LDH-A催化丙酮酸转化为乳酸，这是糖酵解途径的最后一步。虽然 尽管已经报道了一些LDH-A抑制剂，但是没有化合物适合于进一步开发（即，有效的、特异性的、合成上易处理的和代谢上稳定的）。在初步结果中，我们发现了一类新的LDH-A抑制剂，N-羟基吲哚（NHIs）。这些化合物在体外抑制LDH-A，在体内抑制肿瘤生长，并且我们已经收集了表明这些化合物在细胞中抑制LDH-A的多条证据。我们现在希望利用这种新的研究工具，基于NHI的LDH-A抑制剂，开发瓦尔堡效应作为潜在的抗癌策略。瓦尔堡效应是癌细胞依赖有氧糖酵解而不是氧化磷酸化来产生能量的趋势。多行遗传数据表明，LDH-A抑制可以选择性地诱导癌细胞死亡，实际上，如初步结果所述，我们已经进行了多个shRNA实验，强烈表明LDH-A的抑制将是一种有效的抗癌策略。通过所提出的工作，我们打算开发更有效的NHI作为LDH-A抑制剂，评估它们对培养的癌细胞的影响，并在小鼠肿瘤模型中评估它们。通过这项工作，我们打算证明LDH-A的抑制是一种易处理的抗癌策略，并确定候选的实验治疗。

DESCRIPTION (provided by applicant): The objective of the work proposed herein is to develop novel inhibitors of the human enzyme lactate dehydrogenase A (LDH-A). LDH-A catalyzes the conversion of pyruvate to lactate, the final step in the glycolytic pathway. Although a few LDH-A inhibitors have been reported, no compounds are suitable for further development (ie, potent, specific, synthetically tractable, and metabolically stable). In preliminary results w have discovered a novel class of LDH-A inhibitors, the N-hydroxyindoles (NHIs). These compounds inhibit LDH-A in vitro, inhibit tumor growth in vivo, and we have collected multiple lines of evidence indicating these compounds inhibit LDH-A in cells. We now wish to utilize this novel research tool, the NHI- based LDH-A inhibitors, to exploit the Warburg effect as a potential anticancer strategy. The Warburg effect is the tendency of cancer cells to rely on aerobic glycolysis instead of oxidative phosphorylation for energy production. Multiple lines of genetic data suggests that LDH-A inhibition could selectively induce death in cancer cells, and indeed as described in the preliminary results we have conducted multiple shRNA experiments that strongly suggest the inhibition of LDH-A will be an effective anticancer stragegy. Through the work proposed we intend to develop more potent NHIs as LDH-A inhibitors, assess their effect on cancer cells in culture, and evaluate them in murine tumor models. Through this work we intend to demonstrate that the inhibition of LDH-A is a tractable anticancer strategy, and to identify candidate experimental therapeutics.