Tasquinimod Is an Allosteric Modulator of HDAC4 survival signaling within the compromised cancer microenvironment
- Cancer Res. 2013 Feb 15;73(4):1386-99. doi: 10.1158/0008-5472.CAN-12-2730.
- 1. Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, The Johns Hopkins University, 1650 Orleans St., Baltimore, MD 21287, USA. [email protected]
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-1α, 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.