Cini Elena, Faltoni Valentina, Petricci Elena, Taddei Maurizio, Salvini Laura, Giannini Giuseppe, Vesci Loredana, Milazzo Ferdinando Maria, Anastasi Anna Maria, Battistuzzi Gianfranco, De Santis Rita
Lead Discovery Siena srl , Via Fiorentina 1 , 53100 Siena , Italy.
Dipartimento di Biotecnologie , Chimica e Farmacia , Università degli Studi di Siena , Via A. Moro 2 , 53100 Siena , Italy . Email:
Chem Sci. 2018 Jul 3;9(31):6490-6496. doi: 10.1039/c7sc05266a. eCollection 2018 Aug 21.
We describe here two novel antibody-drug conjugates loaded with the HDAC inhibitor ST7612AA1 (IC equal to 0.07 μM on NCI-H460 cells), a thiol-based molecule with a moderate toxicity . Two payloads were prepared using cleavable and non-cleavable linkers. After anchoring to cetuximab through amide bond with lysines, the resulting HDAC inhibitor-antibody conjugates showed ability to recognize EGFR and efficient internalization in tumor cells. Both ADCs induced sensible increment of histones 3 and 4 and alpha-tubulin acetylation. Animal models of human solid tumors showed high anti-tumor efficacy of the conjugates without the toxicity generally observed with traditional ADCs delivering highly potent cytotoxic drugs. These compounds, the first ADCs charged with not highly cytotoxic warheads, are potentially suitable for epigenetic modulation, extending the ADC strategy to the targeted delivery of HDAC inhibitors with many possible therapeutic applications beyond cancer.
我们在此描述了两种新型抗体药物偶联物，其负载有HDAC抑制剂ST7612AA1（对NCI-H460细胞的IC等于0.07μM），这是一种具有中等毒性的基于硫醇的分子。使用可裂解和不可裂解的连接子制备了两种payload。通过与赖氨酸形成酰胺键锚定到西妥昔单抗上后，所得的HDAC抑制剂-抗体偶联物显示出识别EGFR的能力以及在肿瘤细胞中的有效内化。两种ADC均诱导组蛋白3和4以及α-微管蛋白乙酰化的明显增加。人类实体瘤动物模型显示，该偶联物具有高抗肿瘤功效，且没有传统递送高效细胞毒性药物的ADC通常观察到的毒性。这些化合物是首批负载非高细胞毒性弹头的ADC，可能适用于表观遗传调控，将ADC策略扩展到HDAC抑制剂的靶向递送，具有许多癌症以外的可能治疗应用。
