Saraswati A Prasanth, Relitti Nicola, Brindisi Margherita, Osko Jeremy D, Chemi Giulia, Federico Stefano, Grillo Alessandro, Brogi Simone, McCabe Niamh H, Turkington Richard C, Ibrahim Ola, O'Sullivan Jeffrey, Lamponi Stefania, Ghanim Magda, Kelly Vincent P, Zisterer Daniela, Amet Rebecca, Hannon Barroeta Patricia, Vanni Francesca, Ulivieri Cristina, Herp Daniel, Sarno Federica, Di Costanzo Antonella, Saccoccia Fulvio, Ruberti Giovina, Jung Manfred, Altucci Lucia, Gemma Sandra, Butini Stefania, Christianson David W, Campiani Giuseppe
Department of Biotechnology, Chemistry and Pharmacy, DoE Department of Excellence 2018-2022, University of Siena, via Aldo Moro 2, I-53100 Siena, Italy.
Roy and Diana Vagelos Laboratories, Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania 19104-6323, United States.
ACS Med Chem Lett. 2020 Sep 29;11(11):2268-2276. doi: 10.1021/acsmedchemlett.0c00395. eCollection 2020 Nov 12.
Histone deacetylase inhibitors (HDACi) have emerged as promising therapeutics for the treatment of neurodegeneration, cancer, and rare disorders. Herein, we report the development of a series of spiroindoline-based HDAC6 isoform-selective inhibitors based on the X-ray crystal studies of the hit . We identified compound as the most potent and selective HDAC6 inhibitor of the series. Biological investigation of compounds , , and demonstrated their antiproliferative activity against several cancer cell lines. Western blotting studies indicated that they were able to increase tubulin acetylation, without significant variation in histone acetylation state, and induced PARP cleavage indicating their apoptotic potential at the molecular level. induced HDAC6-dependent pSTAT3 inhibition.
组蛋白去乙酰化酶抑制剂（HDACi）已成为治疗神经退行性疾病、癌症和罕见疾病的有前景的治疗药物。在此，我们报告基于命中物的X射线晶体学研究开发的一系列基于螺吲哚啉的HDAC6亚型选择性抑制剂。我们确定化合物 为该系列中最有效和选择性最强的HDAC6抑制剂。对化合物 、 和 的生物学研究表明它们对几种癌细胞系具有抗增殖活性。蛋白质印迹研究表明，它们能够增加微管蛋白乙酰化，而组蛋白乙酰化状态没有显著变化，并诱导PARP裂解，表明它们在分子水平上具有凋亡潜力。 诱导HDAC6依赖性的pSTAT3抑制。
