Discovery of cyanocarbonimidodithioates as novel non-hydroxamate zinc-binding groups for selective HDAC8 inhibition: Design, synthesis, biological evaluation, anticancer activity, and in silico studies.

Authors

Sai Chaitanya Kosana, Hrushikesh Chaudhari, Ashna Fathima, Suryansh Sengar, Markus Schweipert, Yogesh Mahadu Khetmalis, N V M Rao Bandaru, Chandrasekhar Abbineni, Trinath Jamma, Vivek Sharma, Franz-Josef Meyer-Almes, Venkata Gowri Chandra Sekhar Kondapalli

Published in

Bioorganic chemistry. Volume 182. Pages 110551. Sep 17, 2026. Epub Sep 17, 2026.

Abstract

Histone deacetylase 8 (HDAC8) is a promising therapeutic target in cancer; however, the clinically approved hydroxamate-based inhibitors exhibit weak selectivity and undesirable toxicity due to binding at multiple sites. In this work, we report the design and synthesis of a new class of non-hydroxamate HDAC8 inhibitors with an unexplored cyanocarbonimidodithioate zinc-binding group (ZBG). A series of new compounds (SHC 1-3 and AC 1-14) were synthesized by the optimization of the cap groups and linker. SHC-1 and SHC-2 were found to be the most potent and selective HDAC8 inhibitors, with IC₅₀ values of 0.036 μM and 0.041 μM, respectively, and high selectivity for HDAC8 over other HDAC isoforms. SHC-1 showed promising antiproliferative activity in IMR-32 neuroblastoma cells, colony formation inhibition, cell migration inhibition, caspase 3/7 assay and western blot. Mechanistic studies indicated increased SMC3 acetylation, suggesting HDAC8 inhibition. Molecular docking, molecular dynamics simulation, and MM-GBSA showed that SHC-2 binds stably to the HDAC8 active pocket via strong zinc coordination and critical interactions in the enzyme sub-pocket. ADMET predictions indicated good drug-likeness for the new compounds. A crystal of AC-4 was grown, and the structure was confirmed through SC-XRD. In summary, we have developed cyanocarbonimidodithioates as a new non-hydroxamate ZBG. These inhibitors demonstrated encouraging activity and a robust association with reported phenotypic changes, suggesting they could be further developed as cancer therapeutic agents.

PMID:
42767177
Bibliographic data and abstract were imported from PubMed on 22 Sep 2026.

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