6v7a

Publication Abstract from PubMed

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 6a. We identified compound 6j as the most potent and selective hHDAC6 inhibitor of the series. Biological investigation of compounds 6b, 6h, and 6j 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. 6j induced HDAC6-dependent pSTAT3 inhibition.

Spiroindoline-Capped Selective HDAC6 Inhibitors: Design, Synthesis, Structural Analysis, and Biological Evaluation.,Saraswati AP, Relitti N, Brindisi M, Osko JD, Chemi G, Federico S, Grillo A, Brogi S, McCabe NH, Turkington RC, Ibrahim O, O'Sullivan J, Lamponi S, Ghanim M, Kelly VP, Zisterer D, Amet R, Hannon Barroeta P, Vanni F, Ulivieri C, Herp D, Sarno F, Di Costanzo A, Saccoccia F, Ruberti G, Jung M, Altucci L, Gemma S, Butini S, Christianson DW, Campiani G ACS Med Chem Lett. 2020 Sep 29;11(11):2268-2276. doi: , 10.1021/acsmedchemlett.0c00395. eCollection 2020 Nov 12. PMID:33214839^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.