Lactam-Based HDAC Inhibitors for Anticancer Chemotherapy: Restoration of RUNX3 by Posttranslational Modification and Epigenetic Control

Expression and stability of the tumor suppressor runt‐related transcription factor 3 (RUNX3) are regulated by histone deacetylase (HDAC). HDAC inhibition alters epigenetic and posttranslational stability of RUNX3, leading to tumor suppression. However, HDAC inhibitors can nonselectively alter global gene expression through chromatin remodeling. Thus, lactam‐based HDAC inhibitors were screened to identify potent protein stabilizers that maintain RUNX3 stability by acetylation. RUNX activity and HDAC inhibition were determined for 111 lactam‐based analogues through a cell‐based RUNX activation and HDAC inhibition assay. 3‐[1‐(4‐Bromobenzyl)‐2‐oxo‐2,5‐dihydro‐1H‐pyrrol‐3‐yl]‐N‐hydroxypropanamide (11‐8) significantly increased RUNX3 acetylation and stability with relatively low RUNX3 mRNA expression and HDAC inhibitory activity. This compound showed significant antitumor effects, which were stronger than SAHA, in an MKN28 xenograft model. Thus, we propose a novel strategy, in which HDAC inhibitors serve as antitumor chemotherapeutic agents that selectively target epigenetic regulation and protein stability of RUNX3. Keep it RUNning! Epigenetic and posttranslational stabilization of RUNX3 is regulated by HDACs, leading to cancer suppression. Our γ‐lactam‐based HDAC inhibitors restored RUNX3 stability by epigenetic and posttranslational regulation. We set selection criteria for identifying potent HDAC inhibitors and found a novel therapeutic agent for gastric cancer.