Tasquinimod is an allosteric modulator of HDAC4 survival signaling within the compromised cancer microenvironment

John T. Isaacs, Lizamma Antony, Susan L. Dalrymple, W. Nathaniel Brennen, Stephanie Gerber, Hans-Joerg Hammers, Michel Wissing, Sushant Kachhap, Jun Luo, Li Xing, Per Bjork, Anders Olsson, Anders Bjork, Tomas Leanderson

Research output: Contribution to journalArticlepeer-review

60 Scopus citations


Tasquinimod is an orally active antiangiogenic drug that is currently in phase III clinical trials for the treatment of castration-resistant prostate cancer. However, the target of this drug has remained unclear. In this study, we applied diverse strategies to identify the histone deacetylase HDAC4 as a target for the antiangiogenic activity of tasquinimod. Our comprehensive analysis revealed allosteric binding (Kd 10-30 nmol/L) to the regulatory Zn2 binding domain of HDAC4 that locks the protein in a conformation preventing HDAC4/N-CoR/HDAC3 complex formation. This binding inhibited colocalization of N-CoR/HDAC3, thereby inhibiting deacetylation of histones and HDAC4 client transcription factors, such as HIF-1a, which are bound at promoter/enhancers where epigenetic reprogramming is required for cancer cell survival and angiogenic response. Through this mechanism, tasquinimod is effective as a monotherapeutic agent against human prostate, breast, bladder, and colon tumor xenografts, where its efficacy could be further enhanced in combination with a targeted thapsigargin prodrug (G202) that selectively kills tumor endothelial cells. Together, our findings define a mechanism of action of tasquinimod and offer a perspective on how its clinical activity might be leveraged in combination with other drugs that target the tumor microenvironment.

Original languageEnglish (US)
Pages (from-to)1386-1399
Number of pages14
JournalCancer Research
Issue number4
StatePublished - Jan 15 2013

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


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