# Harnessing Substituted 4-Chlorothieno[2,3-b]pyridine as a New Cap for Potent and Selective Antiproliferative HDAC Inhibitors

## TL;DR

This paper introduces new HDAC inhibitors with a 4-chlorothieno[2,3-b]pyridine cap that show high potency and selectivity against cancer cells.

## Contribution

The novel use of substituted 4-chlorothieno[2,3-b]pyridine as a cap for HDAC inhibitors is introduced and tested for antiproliferative activity.

## Key findings

- Compounds 7a and 9a showed GI50 values of 2.15 µM and 1.89 µM, respectively.
- Compound 7a had IC50 values of 0.37 µM, 0.58 µM, and 0.70 µM against HDACs 1, 4, and 6.
- Compound 7a exhibited a selectivity index of 11 for RPMI-8226 cells over PBMCs.

## Abstract

Background: Inhibition of histone deacetylase is a highly sought-after objective in the fight against cancer. Thus, the development of innovative HDAC inhibitors with significantly higher potency than SAHA against specific cancer cell types represents complex and demanding work. Method: The utilization of the underexplored and privileged scaffold 4-chlorothieno[2,3-b]pyridine as a cap tethering diverse aliphatic and aromatic linkers, followed by the screening of both cellular and enzymatic activities, is undertaken in this study. Results: Compounds 7a and 9a demonstrated impressive mean GI50 values of 2.15 µM and 1.89 µM, respectively. Both compounds reduced caspase-3 levels in RPMI-8226 cells, suggesting induction of apoptosis. Compound 7a showed remarkable IC50 values of 0.37 µM, 0.58 µM, and 0.70 µM against HDACs 1, 4, and 6, respectively, consistent with the cellular assay. Additionally, compound 7a exhibited a selectivity index of 11 for RPMI-8226 cells over PBMCs, reflecting its high selectivity and potential safety. Moreover, ADMET prediction tools indicated that compounds 7a and 9b may have more favorable pharmacokinetic properties than the gold-standard HDAC inhibitor, SAHA. Conclusions: Further study and exploration of the derivatives of compounds 7a and 9a can lead to further advancement in the development of potent HDAC inhibitor anticancer drugs.