Hydroxamic acid group is one of the characteristic pharmacophores of histone deacetylase (HDAC) inhibitors. But here, we discovered a series of hydroxamic acid-based microtubule destabilizing agents (MDAs), which were derived from shortening the length of the linker in HDAC6 inhibitor SKLB-23bb. Interestingly, the low nanomolar antiproliferative activity of these MDAs depended on the presence of hydroxamic acid groups, but their inhibitory effects on HDAC were lost. Among them, 12b showed favorable metabolism stability, high bioavailability, and potent antitumor activity in multidrug-resistant cell lines and A2780/T xenograft model. More importantly, in the patient-derived xenograft models of triple-negative breast cancer and osimertinib-resistant non-small-cell lung cancer, both 20 mg/kg oral and 10 mg/kg intravenous administration of 12b could induce more than 70% tumor inhibition without obvious toxicity. Overall, we discovered that 12b, as a novel MDA based on hydroxamic acid, could serve as a potential MDA for further investigation.

中文翻译：

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发现一系列具有强效抗肿瘤活性的基于异羟肟酸的微管去稳定剂

异羟肟酸基团是组蛋白去乙酰化酶 (HDAC) 抑制剂的特征药效团之一。但在这里，我们发现了一系列基于异羟肟酸的微管去稳定剂 (MDA)，它们源自缩短 HDAC6 抑制剂 SKLB-23bb 中接头的长度。有趣的是，这些 MDA 的低纳摩尔抗增殖活性取决于异羟肟酸基团的存在，但它们对 HDAC 的抑制作用消失了。其中，12b在多药耐药细胞系和 A2780/T 异种移植模型中显示出良好的代谢稳定性、高生物利用度和有效的抗肿瘤活性。更重要的是，在三阴性乳腺癌和奥希替尼耐药的非小细胞肺癌患者来源的异种移植模型中，20 mg/kg 口服和 10 mg/kg 静脉给药12b均可诱导超过 70% 的肿瘤抑制无明显毒性。总的来说，我们发现12b作为一种基于异羟肟酸的新型 MDA，可以作为进一步研究的潜在 MDA。