biostudies-literatureMorgen MNCRR NIH HHSArgonne National LaboratoryNational Institutes of HealthNIGMS NIH HHS1163-1174https://www.ebi.ac.uk/biostudies/studies/S-EPMC7335359biostudies-literatureUnknown15(13)We report the synthesis and evaluation of a class of selective multitarget agents for the inhibition of HDAC6, HDAC8, and HDAC10. The concept for this study grew out of a structural analysis of the two selective inhibitors Tubastatin A (HDAC6/10) and PCI-34051 (HDAC8), which we recognized share the same N-benzylindole core. Hybridization of the two inhibitor structures resulted in dihydroxamic acids with benzyl-indole and -indazole core motifs. These substances exhibit potent activity against HDAC6, HDAC8, and HDAC10, while retaining selectivity over HDAC1, HDAC2, and HDAC3. The best substance inhibited the viability of the SK-N-BE(2)C neuroblastoma cell line with an IC₅₀ value similar to a combination treatment with Tubastatin A and PCI-34051. This compound class establishes a ChemMedChemDesign and Synthesis of Dihydroxamic Acids as HDAC6/8/10 Inhibitors.PMC7335359R01 GM049758DE-AC02-06CH11357P30 GM124165GM49758S10 RR029205T32 GM071339Oehme IMiller AKHerbst-Gervasoni CJSteimbach RRChristianson DWRidinger JSehr PPorter NJWitt OOsko JDGunkel NHellweg LMorgen MGeraldy MfalseDesign and Synthesis of Dihydroxamic Acids as HDAC6/8/10 Inhibitors.We report the synthesis and evaluation of a class of selective multitarget agents for the inhibition of HDAC6, HDAC8, and HDAC10. The concept for this study grew out of a structural analysis of the two selective inhibitors Tubastatin A (HDAC6/10) and PCI-34051 (HDAC8), which we recognized share the same N-benzylindole core. Hybridization of the two inhibitor structures resulted in dihydroxamic acids with benzyl-indole and -indazole core motifs. These substances exhibit potent activity against HDAC6, HDAC8, and HDAC10, while retaining selectivity over HDAC1, HDAC2, and HDAC3. The best substance inhibited the viability of the SK-N-BE(2)C neuroblastoma cell line with an IC₅₀ value similar to a combination treatment with Tubastatin A and PCI-34051. This compound class establishes a 2020-01-01T00:00:00Z2020 Jul2026-04-30T05:55:01.253Z2020-07-09T07:01:43ZS-EPMC73353593234862810.1002/cmdc.202000149