Álvarez-Gómez Cristian, Fonseca-Benítez Angela V, Guevara-Pulido James
INQA, Química Farmacéutica, Universidad El Bosque, Bogotá, Colombia.
PLoS One. 2025 Apr 28;20(4):e0319415. doi: 10.1371/journal.pone.0319415. eCollection 2025.
Acute lymphoblastic leukemia (ALL) is a significant concern in both pediatric and adult demographics. Despite 156 approved cancer therapies based on small molecules, a mere five apply to all types of leukemia. Unfortunately, adherence to these treatments is low due to adverse side effects. Consequently, there is an urgent need to identify more effective treatment options for ALL. This study presents a potential solution. We have designed over fifty analogs of carbamazepine, utilizing a combination of ligand-based and structure-based drug design methodologies. Among these analogs, we identified the CR80 analog, which demonstrated predicted binding values of -8.66 kcal/mol against beta-tubulin, a favorable LogP, and IC50 values suitable for in vitro evaluation. The CR80 compound was synthesized with a yield of 50% and subsequently assessed in vitro against the U-937 cell line. It obtained an IC50 value of 0.8 micromolar to 1 micromolar and a selectivity index of two, thus marking it as a promising candidate for in vivo studies.
急性淋巴细胞白血病（ALL）在儿科和成人人群中都是一个重大问题。尽管有156种基于小分子的获批癌症疗法，但仅有5种适用于所有类型的白血病。不幸的是，由于副作用，这些治疗方法的依从性很低。因此，迫切需要为ALL确定更有效的治疗方案。本研究提出了一种潜在的解决方案。我们利用基于配体和基于结构的药物设计方法相结合，设计了五十多种卡马西平类似物。在这些类似物中，我们鉴定出了CR80类似物，它对β-微管蛋白的预测结合值为-8.66千卡/摩尔，具有良好的脂水分配系数（LogP），以及适合体外评估的半数抑制浓度（IC50）值。CR80化合物的合成产率为50%，随后在体外针对U-937细胞系进行了评估。它的IC50值为0.8微摩尔至1微摩尔，选择性指数为2，因此被标记为体内研究的有希望的候选物。
