Journal Article

Targeting the CoREST complex with dual histone deacetylase and demethylase inhibitors

Hu, Yong, Rudek, Michelle A., Wu, Mingxuan, Wu, Muzhou, Alani, Rhoda M., Chung, Hye Jin, Gray, Jeffrey J., Anders, Nicole M., Roberts, Holly J., Prusevich, Polina, Valente, Sergio, Kalin, Jay H., Song, Yun, Hancock, Wayne W., Mai, Antonello, Das, Jayanta, Dinkova-Kostova, Albena T., Proby, Charlotte M., Mattevi, Andrea, Gomez, Andrea V., Adejola, Nkosi, Bradner, James E., Hayward, Dawn, Ryu, Byungwoo, Milano, Charles, Panova, Izabela, Kim, Edward, Roberts, Justin M., Cole, Philip A., Roy Burman, Shourya S., Eroglu, Abdulkerim, Schwabe, John W. R., Jeliazkov, Jeliazko R., Fairall, Louise

2018

Overview

Here we report corin, a synthetic hybrid agent derived from the class I HDAC inhibitor (entinostat) and an LSD1 inhibitor (tranylcypromine analog). Enzymologic analysis reveals that corin potently targets the CoREST complex and shows more sustained inhibition of CoREST complex HDAC activity compared with entinostat. Cell-based experiments demonstrate that corin exhibits a superior anti-proliferative profile against several melanoma lines and cutaneous squamous cell carcinoma lines compared to its parent monofunctional inhibitors but is less toxic to melanocytes and keratinocytes. CoREST knockdown, gene expression, and ChIP studies suggest that corin’s favorable pharmacologic effects may rely on an intact CoREST complex. Corin was also effective in slowing tumor growth in a melanoma mouse xenograft model. These studies highlight the promise of a new class of two-pronged hybrid agents that may show preferential targeting of particular epigenetic regulatory complexes and offer unique therapeutic opportunities. Alteration of the epigenetic landscape has been implicated in several disease processes, where targeting histone modifiers may have therapeutic applications. Here the authors report a bifunctional small molecule inhibitor that simultaneously targets the deacetylase (HDAC1) and demethylase (LSD1) activities of the CoREST complex.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 631/337/100/2285 / 631/45/607/1167 / 631/92/96 / Aged / Animals / Antineoplastic Agents / Benzamides - pharmacology / Cell Line, Tumor / Cell Proliferation / Co-Repressor Proteins - antagonists & inhibitors / Co-Repressor Proteins - metabolism / Drug Design / Drug Screening Assays, Antitumor / Enzymology / Female / Gene expression / Histone deacetylase / Histone Deacetylase Inhibitors - pharmacology / Histone Deacetylases - chemistry / Humanities and Social Sciences / Humans / Inhibitors / Keratinocytes / Male / Melanocytes / Melanoma / Melanoma - drug therapy / Mice / Mice, Inbred BALB C / Mice, Nude / Middle Aged / multidisciplinary / Nerve Tissue Proteins - antagonists & inhibitors / Nerve Tissue Proteins - metabolism / Oligonucleotide Array Sequence Analysis / Pharmacology / Pyridines - pharmacology / Repressor Proteins - antagonists & inhibitors / Repressor Proteins - metabolism / Science / Science (multidisciplinary) / Skin Neoplasms - drug therapy / Squamous cell carcinoma / Tranylcypromine / Tranylcypromine - pharmacology / Xenograft Model Antitumor Assays / Xenografts