Gonçalo Bernardes, Principal Investigator at iMM and co-leader of the study. Credit: Gonçalo Ribeiro, iMM

iMM 首席研究员兼该研究的联合负责人 Gonçalo Bernardes。图片来源：贡萨洛·里贝罗，iMM

Back in 2018, this team used machine learning to identify the targeting site of a compound from the lapacho tree bark that belongs to the family of ortho-quinones, called β-lapachone. These compounds are known for their potential to control the abnormal increase in the number of cells that characterizes cancer and are good candidates for the treatment of leukemia.

早在2018 年，该团队就使用机器学习从属于邻醌家族的 lapacho 树皮中识别出一种化合物的靶向位点，称为 β-lapachone。这些化合物以其控制以癌症为特征的细胞数量异常增加的潜力而闻名，并且是治疗白血病的良好候选者。

“The compound that we explored in this study, called β-lapachone, is a promising drug to treat leukemia, but its reactive properties could have undesirable effects. In this work, we combined two strategies to minimize the negative effects of the compound. On one side, we added a chemical group to this compound that protects from its reactive properties. It acts like a mask that covers the toxicity of the drug. This mask is released in a more acidic environment, that corresponds to the interior of cells. This leads to our second strategy. We attached the modified compound to a protein, an antibody, that delivers it directly to the interior of cancer cells.”, adds Gonçalo Bernardes.

“我们在这项研究中探索的化合物，称为β-lapachone，是一种很有前途的治疗白血病的药物，但它的反应特性可能会产生不良影响。 在这项工作中，我们结合了两种策略来最大限度地减少化合物的负面影响。 一方面，我们在该化合物中添加了一个化学基团，以防止其反应特性。 它就像一个掩盖药物毒性的面具。 这种面膜在更酸性的环境中释放，对应于细胞内部。 这导致了我们的第二个策略。 我们将修饰后的化合物与一种蛋白质（一种抗体）结合，将其直接输送到癌细胞内部。”Gonçalo Bernardes 补充道。

“Cancer cells have certain marks that tell them apart from healthy cells. In acute myeloid leukemia we know that one of these specific markers, called CD33, is present in the cancer cells. We attached our natural product to an antibody that binds specifically to this CD33. This allows the drug to go through the body without damaging any healthy cells and when the antibody encounters the cancer cell, it binds to the CD33 marker and delivers the drug. At this moment it will turn into its active and toxic form, killing the cancer cell”, clarifies Ana Guerreiro, co-second author of the study.

“癌细胞具有某些标记，可以将它们与健康细胞区分开来。在急性髓性白血病中，我们知道癌细胞中存在这些特定标记之一，称为 CD33。 我们将我们的天然产物连接到与该 CD33 特异性结合的抗体上。 这使得药物可以在不损害任何健康细胞的情况下通过身体，当抗体遇到癌细胞时，它会与 CD33 标记物结合并释放药物。 此刻它会变成它的活性和毒性形式，杀死癌细胞”，该研究的共同第二作者 Ana Guerreiro 澄清道。

Besides the therapeutic interest of this approach for the treatment of acute myeloid leukemia, the chemistry that was developed in this study can be used for other valuable natural compounds, enabling the use of compounds with therapeutic potential that were previously inappropriate for medicinal use.

除了这种方法治疗急性髓性白血病的治疗意义外，本研究中开发的化学方法还可用于其他有价值的天然化合物，从而能够使用以前不适合药用的具有治疗潜力的化合物。