Development of a novel lactate dehydrogenase A inhibitor with potent antitumor activity and immune activation

Cancer is a major cause of death around the world and affects millions of individuals globally. Unlike normal cells, cancer cells produce energy by converting sugars (i.e., glucose) to a compound called lactate. This process, famously known as the Warburg effect, leads to lactate accumulation in cancer cells. Subsequently, the elevations in lactate cause multiple adverse effects—including unchecked cell proliferation, increased blood vessel formation, and immune suppression—all of which promote cancer progression. Blocking lactate production, therefore, is a useful strategy in cancer therapy. One way to achieve this is the inhibition of lactate dehydrogenase A (LDHA), an enzyme that aids in lactate production. However, although various LDHA inhibitors have been developed, their efficacy against animal tumors has so far been limited.

Using a series of methods, ranging from cellular assays (in vitro) to animal model (in vivo) experiments, Du et al. designed a novel LDHA inhibitor, ML-05, and tested its efficacy in their study. Their findings revealed that ML-05 could inhibit lactate production in cultured cells quite effectively, thereby reducing the toxic effects of lactate accumulation. Further, the researchers showed that their LDHA inhibitor was capable of arresting cell division at the G1 phase, a crucial checkpoint in the cell cycle, thus preventing uncontrolled cell division.

In addition to the cellular effects, ML-05 also showed strong antitumor effects in mouse models. Interestingly, this effect could be achieved by the direct local injection of ML-05 at the tumor site, without the need for oral intake or systemic administration. ML-05 also increased the population and activity of two specific kinds of immune cells, namely, Th1 and GMZB⁺CD8 T cells, which further amplified its antitumor effects. Moreover, ML-05 also enhanced the antitumor effects of the anti-programmed cell death-1 (PD-1) antibody, an important immunotherapy agent used in cancer treatment.

Taken together, these results show that the novel LDHA inhibitor, ML-05, is an immensely potent antitumor agent, both in vitro and in vivo. Additionally, the study suggests that ML-05 can enhance the effects of immunotherapy, and consequently, it carries a significant translational value.

https://onlinelibrary.wiley.com/doi/full/10.1111/cas.15468

中文翻译：

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在这个问题上

开发具有强效抗肿瘤活性和免疫激活作用的新型乳酸脱氢酶 A 抑制剂

癌症是全世界死亡的主要原因，影响着全球数百万人。与正常细胞不同，癌细胞通过将糖（即葡萄糖）转化为一种称为乳酸的化合物来产生能量。这个过程，众所周知的Warburg效应，会导致癌细胞中乳酸的积累。随后，乳酸升高会导致多种不良反应——包括不受控制的细胞增殖、血管形成增加和免疫抑制——所有这些都会促进癌症进展。因此，阻断乳酸的产生是癌症治疗中的一种有用策略。实现这一目标的一种方法是抑制乳酸脱氢酶 A (LDHA)，这是一种有助于乳酸产生的酶。然而，尽管已经开发了各种 LDHA 抑制剂，但迄今为止它们对动物肿瘤的功效仍然有限。

使用一系列方法，从细胞试验（体外）到动物模型（体内）实验，Du 等人。设计了一种新型 LDHA 抑制剂 ML-05，并在他们的研究中测试了其功效。他们的研究结果表明，ML-05 可以非常有效地抑制培养细胞中乳酸的产生，从而减少乳酸积累的毒性作用。此外，研究人员表明，他们的 LDHA 抑制剂能够在 G1 期（细胞周期的关键检查点）阻止细胞分裂，从而防止不受控制的细胞分裂。

除了细胞作用外，ML-05 在小鼠模型中也表现出很强的抗肿瘤作用。有趣的是，这种效果可以通过在肿瘤部位直接局部注射 ML-05 来实现，而不需要口服或全身给药。ML-05还增加了两种特定免疫细胞，即Th1和GMZB ⁺ CD8 T细胞的数量和活性，进一步放大了其抗肿瘤作用。此外，ML-05 还增强了抗程序性细胞死亡 1 (PD-1) 抗体的抗肿瘤作用，PD-1 是一种用于癌症治疗的重要免疫治疗药物。

总之，这些结果表明新型 LDHA 抑制剂 ML-05 在体外和体内都是一种非常有效的抗肿瘤剂。此外，该研究表明 ML-05 可以增强免疫疗法的效果，因此具有重要的转化价值。

https://onlinelibrary.wiley.com/doi/full/10.1111/cas.15468