Design, Synthesis, and Evaluation of Lactate Dehydrogenase Inhibitors

描述(由申请人提供)：本文提出的工作的目标是开发新型的人类乳酸脱氢酶A(LDH-A)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 已有一些LDH-A抑制剂的报道，没有一种化合物适合于进一步开发(即有效、特异、合成容易处理和代谢稳定)。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，我们收集了多条证据表明这些化合物抑制细胞中的LDH-A。我们现在希望利用这一新的研究工具，基于NHI的LDH-A抑制剂，来开发Warburg效应作为潜在的抗癌策略。Warburg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。多条遗传数据表明，抑制LDH-A可以选择性地诱导癌细胞死亡，事实上，正如初步结果所描述的那样，我们已经进行了多个shRNA实验，强烈表明抑制LDH-A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，评估它们在培养的癌细胞中的作用，并在小鼠肿瘤模型中评估它们。通过这项工作，我们打算证明抑制LDH-A是一种易于处理的抗癌策略，并寻找候选的实验疗法。

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.