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Tasquinimod Is an Allosteric Modulator of HDAC4 survival signaling within the compromised cancer microenvironment.


ABSTRACT: 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 Zn(2+) 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-1?, 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. Cancer Res; 73(4); 1386-99. ©2012 AACR.

SUBMITTER: Isaacs JT 

PROVIDER: S-EPMC3578133 | biostudies-literature | 2013 Feb

REPOSITORIES: biostudies-literature

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Tasquinimod Is an Allosteric Modulator of HDAC4 survival signaling within the compromised cancer microenvironment.

Isaacs John T JT   Antony Lizamma L   Dalrymple Susan L SL   Brennen W Nathaniel WN   Gerber Stephanie S   Hammers Hans H   Wissing Michel M   Kachhap Sushant S   Luo Jun J   Xing Li L   Björk Per P   Olsson Anders A   Björk Anders A   Leanderson Tomas T  

Cancer research 20121113 4


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 Zn(2+) binding domain of HDAC4 that locks the pro  ...[more]

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