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.
Bibliographical noteFunding Information:
Support from the European Union’s Horizon 2020 (EU) Research and Innovation Programme under the Marie Sklodowska-Curie grant agreement No. 721906-TRACT is acknowledged. Cost Action EPICHEMBIO CM1406 (G.C, M.B.) and the synchrotron beamline staff at the Advanced Photon Source (APS) for assistance, especially David Neau are also gratefully acknowledged. We thank the Northeastern Collaborative Access Team (NE-CAT) funded by the National Institute of General Medical Sciences (NIGMS) from the NIH (P30 GM124165), and US National Institutes of Health grant GM49758. The Pilatus 6M detector on beamline 24-ID-C is funded by a NIH-ORIP HEI grant (S10 RR029205). This research used resources of the Advanced Photon Source (APS), a U.S. Department of Energy (DOE) Office of Science User Facility operated for the DOE Office of Science by Argonne National Laboratory under Contract No. DE-AC02-06CH11357. N.R. Tuscany strategic project POR-FSE 2014-2020, ‘Medicina di Precisione e Malattie Rare’(MePreMaRe), (ACE-ESCC). G.R. acknowledges the CNR-CNCCS “Rare, Neglected and Poverty Related Diseases - Schistodiscovery Project” (DSB.AD011.001.003). L.A. acknowledges MIUR20152TE5PK; VALERE: Vanvitelli per la Ricerca; Campania Regional Government Technology Platform Lotta alle Patologie Oncologiche: iCURE and Campania Regional Government FASE2: IDEAL. MIUR, Proof of Concept POC01_00043.
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- cancer therapy
- HDAC inhibitors
ASJC Scopus subject areas
- Drug Discovery
- Organic Chemistry