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Assays for Validating Histone Acetyltransferase Inhibitors
09:11

Assays for Validating Histone Acetyltransferase Inhibitors

Published on: August 6, 2020

Cancer network disruption by a single molecule inhibitor targeting both histone deacetylase activity and

Changgeng Qian1, Cheng-Jung Lai, Rudi Bao

  • 1Curis, Inc., Lexington, Massachusetts 02421, USA.

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
|June 14, 2012
PubMed
Abstract

Insights

A new dual-acting drug, CUDC-907, simultaneously inhibits histone deacetylase (HDAC) and phosphatidylinositol 3-kinase (PI3K) enzymes. This dual inhibition shows greater anticancer activity than single-target drugs by disrupting multiple cancer signaling pathways.

Area of Science:

  • Oncology
  • Pharmacology
  • Epigenetics

Background:

  • Histone deacetylase (HDAC) inhibitors trigger epigenetic changes impacting cancer signaling networks.
  • HDAC inhibitors demonstrate synergistic effects when combined with phosphatidylinositol 3-kinase (PI3K) inhibitors.
  • Simultaneous inhibition of HDAC and PI3K presents a promising strategy for cancer therapy.

Purpose of the Study:

  • To develop a dual-acting inhibitor targeting both HDAC and PI3K enzymes in cancer cells.
  • To evaluate the pharmacologic properties, anticancer efficacy, and mechanism of action of a novel dual inhibitor, CUDC-907.
  • To investigate the potential of simultaneous PI3K and HDAC inhibition for improved cancer treatment.

Main Methods:

  • Designed dual-acting inhibitors by integrating HDAC inhibitory features into a PI3K inhibitor structure.
  • Selected and characterized CUDC-907, a dual-acting inhibitor, through in vitro and in vivo studies.
  • Assessed the inhibition of key signaling pathways, including PI3K-AKT-mTOR, RAF, MEK, MAPK, and STAT-3.

Main Results:

  • CUDC-907 effectively inhibits class I PI3Ks and classes I and II HDACs.
  • The drug durably suppresses the PI3K-AKT-mTOR pathway and related signaling molecules, including receptor tyrosine kinases.
  • CUDC-907 demonstrated superior growth inhibition and proapoptotic effects compared to single-target inhibitors in cancer models.

Conclusions:

  • CUDC-907 offers potential therapeutic advantages by simultaneously disrupting multiple oncogenic signaling networks.
  • Sustained inhibition of these pathways by CUDC-907 may lead to improved treatment outcomes.
  • Dual-targeting of PI3K and HDAC represents a viable strategy for enhancing anticancer efficacy.

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